Epilepsiu, 4O(Suppl.
6):S9-S 12, 1999
Lippincott Williams & Wilkins, Philadelphia
0 International League Against Epilepsy
Options After the First Antiepileptic Drug Has Failed
Christian E. Elger and Guillkn FernAndez
Department of Epileptology, University of Bonn, Bonn, Germany
Summary: Long-term antiepileptic drug (AED) treatment is
the standard therapy for epilepsies. In about 60% of patients,
the first AED tried usually leads to seizure control. After failure
of the first AED, it is important to achieve seizure control
rapidly and without side effects. Combining the first drug with
an add-on drug appears to be more effective than a second
monotherapy. However, no scientifically based data are avail-
able that favor any particular drug combination. Along with
pharmacokinetic considerations, clinical experience is an im-
portant determinant in choosing a second AED for use as an
add-on. The time needed to introduce a particular AED is a
further consideration. The simultaneous introduction of two
The standard therapy for epilepsy is antiepileptic drug
(AED) treatment. This is long-term therapy. In 1990, a
10-week survey of French physicians treating patients
with epilepsy revealed that one-third of patients were
given AED therapy for more than 30 years, 40% of pa-
tients were treated for 10-30 years, and 60% of patients
were prescribed antiepileptic medication for 1-10 years
(Table 1) (1).
Antiepileptic treatment is effective in more than 60%
of all epileptic patients because the first drug usually
leads to seizure control and because it does not really
matter which AED is used (2). Idiopathic epilepsies are
an exception because, in specific syndromes, certain
drugs are more effective than others or, conversely, pro-
voke further seizures. The percentage of seizure control
in patients with idiopathic epilepsies is generally higher
than that in focal epilepsies. Reflecting the fact that about
60% of epileptic patients are easily treated with one
AED, almost 60% of patients treated by physicians in
private practice or neurologic clinics receive mono-
therapy (Table 1) (1). In contrast, epileptic patients who
are not treated successfully by a first AED have a dra-
matically reduced rate of seizure control with any other
AED, either as monotherapy or as polytherapy. These
patients are more commonly treated in centers specializ-
Address correspondence and reprint requests to Dr. C. E. Elger at
Klinik fur Epileptologie, 53 105 Bonn, Germany.
s9
add-on drugs, one requiring slow titration and one permitting
rapid introduction, may be a useful strategy. If the quickly
introduced drug is effective as an add-on, introduction of a
slowly titrated second add-on can be obviated. If the quickly
introduced drug reduces seizure frequency, the patient’s quality
of life is improved during titration of the second add-on. If the
second, slowly titrated drug is more effective than the quickly
introduced one, the less-effective drug can be withdrawn. This
strategy also allows a direct comparison between two add-on
drugs at the same time. Key Words: Antiepileptic drugs-
Add-on therapy-Seizure control-Epilepsy.
ing in epilepsy; hence, the rate of monotherapy is much
lower in specialized centers (Table 1) (1).
FAILURE OF THE FIRST
ANTIEPILEPTIC DRUG
When a first AED has failed to control seizure activity,
patients are disappointed and usually have a rather criti-
cal attitude toward any further drug treatment. To regain
the patient’s confidence, the physician needs to formu-
late treatment that will lead to seizure control in a short
time and without side effects. The first question after
failure of the initial AED is whether to continue with
another monotherapy or to introduce a second AED as an
add-on agent. The lower risk for side effects, better cost
effectjveness, and generally better compliance are rea-
sons for replacing the first monotherapy with another.
However, some epileptic syndromes need a combination
of two drugs with complementary effects. Furthermore,
two-drug combinations are generally more effective than
a single drug (3-6). Therefore, polytherapy is often used
in patients in whom monotherapy has failed to produce
seizure control.
WHICH AED SHOULD BE USED AS
AN ADD-ON?
Are there any criteria for choosing the second AED for
polytherapy? In theory, such a decision could be based
 SIO c. E. ELGER AND G. FERNANDEZ
TABLE 1. Number and percentage of patients treated with
AED monotherapy differentiated according to type of
medical institution, and number and percentage of patients
receiving AED treatment differentiated according to duration
of treatment
Patients on monotherapy n %
Private practice 1610
Neurologic clinics 2103
Specialized centers
783
Duration of treatment Years
~~~ ~
<1
1-10
10-30
>30
Adapted from Vespignani et al. (1)
on data from controlled clinical trials, on specific patho-
physiology and basic mechanisms of drug action, on
pharmacokinetic data, and on the physician’s own expe-
rience in prescribing a certain drug. In reality, there has
been no systematic, well-controlled, large-scale study
comparing the effectiveness of different add-on thera-
pies. Current knowledge of the pathophysiology of epi-
lepsy and of drug mechanisms is immense but inconsis-
tent. Therefore, no rational basis for the therapeutic
choice of an add-on drug can yet be derived from basic
neuroscience data.
CONTROLLED CLINICAL DATA
What data are available to support the choice of an
AED to be used after failure of the first drug? Mattson
(4) showed that 70% of 471 patients with newly diag-
nosed epilepsy were adequately treated with mono-
therapy. This author also demonstrated that seizures were
well controlled in an additional 10% and 5% of patients
by the combination of two and three AEDs, respectively.
Therefore, anticonvulsant treatment using monotherapy
and polytherapy led to an unsatisfactory outcome in only
15% of the cohort studied. In addition, polytherapy was
generally more effective than monotherapy in about 15%
of patients with newly diagnosed epilepsy. A similar re-
sult was achieved by Walker and Coone (6) in a smaller
sample of patients, specifically for carbamazepine and
valproate. Good seizure control was achieved with car-
bamazepine monotherapy in 43% and with valproate
monotherapy in 12% of patients. However, 81% of pa-
tients investigated in this study were satisfactorily treated
by a combination of carbamazepine and valproate. Hak-
karainen (7) compared the effectiveness of carbamaze-
pine and phenytoin in 100 patients with newly diagnosed
epilepsy. In the first year of treatment, 52% of patients
treated with carbamazepine and 42% of patients treated
with phenytoin were seizure free. In the second year,
Hakkarainen noted that 16% of patients treated with car-
Epilepsia, Vol. 40, Suppl. 6, 1999
bamazepine and 18% of patients treated with phenytoin
definitely were not responding to therapy. Hakkarainen
went on to treat these nonresponders with a combination
of carbamazepine and phenytoin during the third year of
the trial. This combination led to good seizure control in
five previously nonresponding patients (1 5%).
55 To sum up, these clinical data may support the as-
59
sumption that a combination of AEDs is more effective
35
than monotherapy for prevention of seizures in patients
%
for whom a first AED has failed to control seizure oc-
62 currence. However, a conclusion regarding which AEDs
60
40
should be combined cannot be based on these data.
33
PHARMACODYNAMICS
Some basic mechanisms of AED action are well
known. For example, carbamazepine, phenytoin, valpro-
ate, and lamotrigine interact with sodium channels by
reducing their conductance. Furthermore, vigabatrin, ti-
agabine, benzodiazepines, and phenobarbital are GABA
agonists, and valproate, gabapentin, and topiramate are
also thought to interact with the action of GABA. Other
studies have shown further mechanisms of action [e.g.,
N-methyl-D-aspartate (NMDA) interaction for topira-
mate, felbamate, and gabapentin] (8). However, no com-
parative, controlled drug studies are currently available
that would allow inferences about the ideal drug combi-
nation for preventing seizure occurrence on the basis of
pharrnacodynamic mechanism. Testing different combi-
nations of AEDs in animal models, Bourgeois (9)
showed that carbamazepine plus primidone, valproate
plus clonazepam, and phenytoin plus valproate exhibit
more than additive effects in controlling seizure occur-
rence; however, the last combination also increased neu-
rotoxicity (Table 2). Three further combinations (carba-
mazepine plus valproate, valproate plus ethosuximide,
and phenytoin plus phenobarbital) showed additive ef-
fectiveness with reduced neurotoxicity (Table 2). In con-
trast, phenytoin plus carbamazepine and carbamazepine
TABLE 2. Favorable, fair, and unfavorable combinations of
AEDs based on experience and comfort
Favorable Fair Unfavorable
VPA + ETH CBZ + VPA PHT + CBZ
All“ + VGB (PHT’) CBZ + PBPRM VPA + PBPRM
All + LTG (VPA,h CBZ’) PHT + VPA
All + TPM (PBPRM,h PHT + PB’PRM
CLB~)
All + GBP VPA + PB
(50-100 mg/day)
VPA + CLN
CBZ, carbamazepine; CLB, clobazam; CLN, clonazepam; ETH,
ethosuximide; GBP, gabapentin; LTG, lamotrigine; PB, phenobarbital;
PHT, phenytoin; PRM, primidone; TPM, topiramate; VGB, vigabatrin;
VPA, valproate.
a CBZ, PHT, VPA, PB, PRM.
Cognitive or psychiatric problems may occur.
 OPTIONS AFTER TREATMENT FAlLURE
plus phenobarbital had additive effectiveness but also
additive neurotoxicity, and these drugs are therefore less
satisfactory combinations, as tested in an animal model
(Table 2).
PHARMACOKINETICS
Pharmacokinetic factors constitute an important con-
sideration in the decision about which AED should be
used as an add-on medication, because these factors de-
termine convenience of handling. Carbamazepine, phe-
nytoin, phenobarbital, and primidone are enzyme induc-
tors, whereas valproate and lamotrigine inhibit glucuron-
idation. High percentages of phenytoin, valproate, and
lamotrigine are protein-bound; therefore, their distribu-
tion must be considered when they are used in combina-
tion. Because gabapentin, vigabatrin, and topiramate are
eliminated without undergoing metabolism and are not
protein-bound, their pharmacokinetic features appear to
be ideal for polytherapy. However, gabapentin and tiaga-
bine have short half-lives, making dosing less convenient
(at least three daily doses), and their plasma levels are
less stable (8).
SIDE EFFECTS
Some side effects are so common or so severe that
they should be taken into account before the choice of a
suitable AED is made. Felbamate, carbamazepine, and
valproate may cause bone marrow dyscrasias or even
p-.iFi p
2400mg 2000mg 3600ml
0 1 2 3 4 5
Fig. 1. Length of time needed to titrate a second-line AED up to a commonly used daily dosage. GBP, gabapentin; VGB, vigabatrin;
FBM,felbamate; TGB, tiagabine; TPM, topiramate; LTG, lamotrigine. Dosage specified is daily dosage.
SII
aplastic anemia. Severe hepatic disturbances may be
caused by felbamate or valproate. Phenobarbital, primi-
done, tiagabine, topiramate, benzodiazepines, and carba-
mazepine (in elderly patients) may induce cognitive and
behavioral impairments. Cosmetic problems may be
caused by valproate, vigabatrin (e.g., weight gain), and
phenytoin (e.g., gingival hyperplasia, coarsening of fa-
cial features, acne). Up to 10% of patients who receive
vigabatrin develop mood changes, and about 4% of pa-
tients who receive vigabatrin develop paranoid and psy-
chotic symptoms (1 0,ll).
INTRODUCTION OF ADD-ON THERAPY
As noted above, rapid seizure control is very important
in regaining the patient’s confidence after failure of the
first anticonvulsant treatment. Therefore, the time re-
quired for titration of a second AED to an effective dos-
age is an important factor in the choice of an add-on
drug. Titration for gabapentin and vigabatrin requires
much less time than for topiramate and lamotrigine (Fig.
1). The introduction of two add-on drugs at the same
time, one (e.g., gabapentin) with a short and one (e.g.,
lamotrigine) with a long duration of titration, may be a
good strategy. If the quickly introduced drug is effective
as an add-on, the introduction of the slowly titrated sec-
ond add-on can be stopped. If the quickly introduced
drug reduces seizure frequency, this reduction improves
the quality of life during the introduction of the second
35mg
WFi
400mg 400mg
6 7 8 9 10
weeks
Epilepsia, Vol. 40, Suppl. 6, 1999
s12 c. E. ELGER AND G. FERNANDEZ
add-on. If the second, slowly titrated drug is more effec-
tive than the quickly introduced one, the less-effective
drug should be withdrawn. This strategy allows a direct
comparison between two add-on drugs at the same time.
CLINICAL EXPERIENCE AND PRACTICAL
CONSIDERATIONS
Clinical experience and specific considerations in in-
dividual patients are major factors in the decision of
which drug should be used for add-on treatment, because
very few reliable data exist to support the superiority of
any given drug in terms of efficacy vs. side effects (the
use of valproate in certain idiopathic epilepsies is one
exception). In practice, the epileptic syndrome, the po-
tential for interaction between the first and the second
AED, the speed of titration, and the individual patient
should be considered.
As a practical recommendation, vigabatrin or gaba-
pentin is a good candidate for add-on therapy if carba-
mazepine, phenytoin, or valproate alone has failed to
prevent the occurrence of seizures. A second, slowly
titrated add-on drug (e.g., lamotrigine or topiramate) can
be introduced simultaneously with the introduction of the
first add-on. Unsuccessful or unnecessary drugs should
be withdrawn to avoid use of three, four, or even more
AEDs.
In summary, no controlled data are available to indi-
cate which drug should be used as an effective add-on
treatment. New AEDs (e.g., gabapentin, lamotrigine, ti-
agabine, topiramate, and vigabatrin) offer better pharma-
cokinetic properties than established ones (e.g., carba-
mazepine, phenobarbital, phenytoin, primidone, and val-
proate). Gabapentin and vigabatrin provide a short
duration of titration up to an effective dosage and have
little potential for interaction. Therefore, they seem to be
the first choices for an anticonvulsant add-on drug.
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