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Seizure 2002; 11: 349–351

doi:10.1053/seiz.2002.0711, available online at http://www.idealibrary.com on

Seizure freedom with more than one antiepileptic drug

LINDA J. STEPHEN & MARTIN J. BRODIE

Epilepsy Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow,
Scotland

Correspondence to: Professor M. J. Brodie, Epilepsy Unit, Department of Medicine and Therapeutics, Western
Infirmary, Glasgow G11 6NT, Scotland. E-mail: Martin.J.Brodie@clinmed.gla.ac.uk

Many people with epilepsy take antiepileptic drug (AED) polytherapy, although supportive evidence for the success of this
strategy is sparse. Of 2881 treated patients registered in our database, 1617 (56%) have been seizure-free for at least the previous
year, with 21% taking more than one AED (287 on two, 86%; 42 on three, 13%; 3 on four, 1%). There were 40 effective
duotherapies and 28 triple therapies. Treatment with two or three but not four AEDs may be a useful therapeutic option for
patients not responding to monotherapy. Further explorations of the best regimens for individual seizure types and epilepsy
syndromes is required.
c 2002 BEA Trading Ltd. Published by Elsevier Science Ltd. All rights reserved.

Key words: seizure; antiepileptic drug; combination; epilepsy; pharmacology.

INTRODUCTION PATIENTS

Antiepileptic drugs (AEDs) are the mainstay of
treatment for people with epilepsy. Around 60%
of patients with newly diagnosed epilepsy will be
controlled with the first or second AED 1 , often
at modest or moderate dosing 2 . Once two drugs
have failed, however, the chance of seizure freedom
with further monotherapy options is very low 3 . This
suggests that a substantial number of patients will
receive treatment with two or more AEDs. The
literature has tended to focus on the disadvantages
rather than the successes of polytherapy in epileptic
patients 4 .
There are surprisingly few data to guide clinicians
on strategies for combining AEDs despite the intro-
duction of nine new agents over the last decade. With
advances in the understanding of the pathophysiology
of seizure initiation and propagation 5 and the modes
of AED action 6 , the scope for rational polytherapy
is increasing 7 . There is an emerging consensus that
combining AEDs based on mechanism of action may
enhance effectiveness 8, 9 . This report documents the
different polytherapy regimens taken by seizure-free
patients attending the Epilepsy Unit at the Western
Infirmary in Glasgow, Scotland.
The population consisted of consecutive patients
referred to the Epilepsy Unit from January 1,
1984. At the initial appointment, demographic and
clinical information were obtained from the patient
and any witnesses to the seizures using a struc-
tured questionnaire. These data together with results
of subsequent investigations were entered into a
database. Classification of seizure type and/or epilepsy
syndrome was carried out according to the guidelines
of the International League Against Epilepsy 10 .
AED choice depended on seizure type or epilepsy
syndrome taking into consideration the mechanism of
action and the side-effect and interaction profiles 11 .
Patients were seen every 4–6 weeks, or sooner if
indicated. At each visit response to treatment and
any adverse events were recorded. Compliance was
monitored by measuring circulating AED levels.
Doses were adjusted according to clinical response.
The original drug was substituted if seizure control
was not obtained despite optimal dosing or if the
patient complained of intolerable side-effects. A
combination of drugs was used in patients in whom
seizure freedom proved elusive despite treatment with
one, two or sometimes three monotherapy options.

1059–1311/02/060349 + 03 $35.00/0 c 2002 BEA Trading Ltd. Published by Elsevier Science Ltd. All rights reserved.

350 L. J. Stephen & M. J. Brodie

Table 1: Commonest duotherapy regimens.

AED combination Patients with localization- Patients with primary Total (%)
related seizures (%) generalized seizures (%)

Lamotrigine/sodium valproate 33 (60) 22 (40) 55 (100)

Phenytoin/phenobarbital 23 (79) 6 (21) 29 (100)
Carbamazepine/gabapentin 20 (80) 5 (20) 25 (100)
Carbamazepine/sodium valproate 15 (63) 9 (37) 24 (100)
Carbamazepine/lamotrigine 9 (64) 5 (36) 14 (100)
Phenytoin/carbamazepine 3 (23) 10 (77) 13 (100)
Phenobarbital/carbamazepine 6 (55) 5 (45) 11 (100)
Carbamazepine/vigabatrin 4 (36) 7 (64) 11 (100)
Lamotrigine/topiramate 6 (55) 5 (45) 11 (100)
Carbamazepine/topiramate 7 (70) 3 (30) 10 (100)
Patients taking 30 other combinations 34 (40) 50 (60) 84 (100)
Number of seizure-free patients 160 (55) 127 (45) 287 (100)

When necessary a sequence of combinations was tried

Table 2: Mean doses and ranges for commonest
with the aim of achieving complete seizure control. duotherapies.
For patients uncontrolled with two AEDs, a third and Combination Mean dose (mg) Dose ranges (mg)
sometimes a fourth AED was added. Seizure freedom
Sodium valproate 1253 200–3000
was defined as absence of seizures or auras for at least Lamotrigine 139 25–500
the previous year on unchanged medication. Phenobarbital 137 30–300
Phenytoin 315 100–650
Carbamazepine 672 200–1600
RESULTS Gabapentin 1764 300–6400
Carbamazepine 969 400–2000
At the time of analysis (January–March 2000), 2881 Sodium valproate 2960 300–4000

patients were receiving AED treatment. Of these, Carbamazepine 882 400–1400

Lamotrigine 382 50–600
1617 (56%) had been seizure-free for at least the
Phenytoin 335 200–425
previous year, with 1285 (79%) being controlled with Carbamazepine 795 100–1600
a single AED. The remaining 332 (21%) patients (166 Phenobarbital 148 50–240
of both sexes, median 49 years, age range 14–85 years) Carbamazepine 682 300–1200

took more than one AED. The majority of these were Carbamazepine 910 500–1800
Vigabatrin 1985 600–3000
controlled with two (n = 287, 86%), or three (n = 42,
Lamotrigine 557 300–900
13%) AEDs. Just three seizure-free patients (1%) were Topiramate 230 50–600
taking four drugs. Overall, 192 (58%) patients taking Carbamazepine 980 600–1600
polytherapy had partial and/or secondary generalized Topiramate 347 75–800

seizures. The remaining 140 (42%) patients reported

primary generalized seizures (120 tonic–clonic, 15 Table 3: Commonest successful triple therapy schedules.
myoclonic, five absence). Thirty-nine (12%) patients AED combinations Patients
also had learning disability.
Sodium valproate/lamotrigine/topiramate 5
There were 40 effective duotherapy regimens, the Primidone/carbamazepine/topiramate 3
Carbamazepine/sodium valproate/lamotrigine 3
commonest being sodium valproate with lamotrigine
Carbamazepine/topiramate/clobazam 2
and phenobarbital with phenytoin (Table 1). Mean Carbamazepine/gabapentin/topiramate 2
Carbamazepine/sodium valproate/clobazam 2
doses and ranges for the ten most successful duother- Phenobarbital/sodium valproate/lamotrigine 2
apies are listed in Table 2. Twenty-eight triple therapy Phenobarbital/phenytoin/lamotrigine 2
Phenobarbital/carbamazepine/sodium valproate 2
schedules resulted in seizure freedom, most frequently
Patients taking 19 other combinations 19
sodium valproate with lamotrigine and topiramate
Number of seizure-free patients 42
(Table 3).
Seizure freedom
DISCUSSION
Overall, 56% of the treated patients had been seizure-
free for the previous year on unchanged drug dosage at
the time of analysis. This included some with epilepsy
already refractory to AEDs at referral as well as others
initially diagnosed and treated at the Epilepsy Unit.
The majority of patients controlled on combination
treatment took just two AEDs. A further 42 patients
responded to three AEDs, but only three patients were
successfully managed with four drugs.
With the expanding array of AEDs with different
mechanisms of action, a much wider range of
pharmacological options is now available 6 . The
commonest efficacious duotherapy in this study was
sodium valproate with lamotrigine, which has been
reported to have greater efficacy for partial and tonic–
clonic seizures than phenytoin or carbamazepine
with lamotrigine 12 . Evidence is accumulating in
support of synergism with these two drugs which
may have a pharmacodynamic as well as a phar-
macokinetic basis 13 . The number of seizure-free
patients talking phenobarbital with phenytoin reflects
previous experience 14, 15 . Doses employed in the
various duotherapy regimens varied widely suggesting
substantial variation in response.
Treating patients with refractory epilepsy provides a
major therapeutic challenge. This survey supports our
previous observations in patients with symptomatic
and cryptogenic epilepsy 16 that combining two or at
most three AEDs may be a useful therapeutic option
when monotherapy fails. The wide range of effective
combinations suggests substantial pathophysiologi-
cal diversity in the causation of difficult-to-control
epilepsy. Further exploration of the best regimens for
individual seizure types and epilepsy syndromes is
required. We believe that combination therapy using
drugs with potentially complementary modes of action
forms an essential component of a staged approach to
the management of difficult-to-control epilepsy 17 .
351
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