european journal of paediatric neurology 13 (2009) 493504

Official Journal of the European Paediatric Neurology Society

Review article

Treatment of Lennox-Gastaut Syndrome (LGS)

Colin D. Ferriea,*, Amit Patelb
a

Department of Paediatric Neurology, Clarendon Wing, Leeds General Infirmary, Leeds LS2 9NS, UK
UK Medical Advisor, Eisai Ltd, Hatfield, UK

article info

abstract

Article history:

Lennox-Gastaut Syndrome (LGS) is a severe form of epilepsy that usually starts in early to

Received 24 September 2007

mid childhood and is characterized by multiple seizure types, abnormal electroencepha-

Received in revised form

logram with slow spike-and-wave discharges and cognitive problems. Numerous

3 March 2008

approaches are currently used to treat LGS, including use of conventional antiepileptic

Accepted 27 December 2008

drugs (most commonly sodium valproate, lamotrigine and topiramate), other drug interventions (corticosteroids and intravenous immunoglobulin) and nonpharmacologic treat-

Keywords:

ments (ketogenic diet, corpus callosotomy and vagus nerve stimulation). Rufinamide is the

Epilepsy

most recent antiepileptic drug to have shown efficacy in the treatment of LGS.

Child

Despite the variety of therapeutic options, there have been only five double-blind, placebo-

Epileptic encephalopathy

controlled clinical trials of antiepileptic drugs in LGS and none of these were head-to-head

Antiepileptic drug

comparison trials. The evidence supporting the use of available treatments for LGS is,

Management

therefore, not robust. Here, we review the evidence supporting the use of specific therapies
in LGS and provide recommendations on how to set appropriate treatment goals, select
treatments and minimize polypharmacy. A suggested treatment algorithm is presented
and discussed. Sodium valproate is recommended for first-line therapy; if seizures persist,
alternative interventions should be trialed on an individually tailored basis.
2009 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights
reserved.

Contents
1.

2.

What
1.1.
1.2.
1.3.

is Lennox-Gastaut Syndrome? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Definition and diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Classification and causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3.1. Symptomatic and probably symptomatic (cryptogenic) LGS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3.2. Idiopathic LGS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.4. Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
What therapies are available to treat LGS? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. Conventional antiepileptic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.1. Evidence from double-blind, placebo-controlled clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.2. Evidence from uncontrolled studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2. Other drug treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.1. Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.2. Intravenous immunoglobulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

* Corresponding author.
1090-3798/$ see front matter 2009 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.ejpn.2008.12.005

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european journal of paediatric neurology 13 (2009) 493504

2.3.

3.

4.

Nonpharmacologic interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.1. Ketogenic diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.2. Corpus callosotomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.3. Vagus nerve stimulation (VNS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
How should LGS be treated? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Review prior and existing medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2. Develop treatment goals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3. Introduce treatment interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.

What is Lennox-Gastaut Syndrome?

1.1.

Epidemiology

Lennox-Gastaut Syndrome (LGS) is a rare childhood epileptic

encephalopathy estimated to affect up to 2 in 10,000 people in
Europe.1 The prevalence of LGS amongst children with epilepsy
has been reported to be 36%,24 although this estimate probably reflects a very broad definition of the syndrome. If strict
diagnostic criteria are used, the prevalence is 3%.5 Males are
affected up to five times more often than females.1 Symptoms
usually start between 3 and 5 years of age but may appear
earlier, while onset after 10 years of age is rare.6 Although there
have been reports of LGS being diagnosed in adults, the
appropriateness of such diagnoses may be questioned.7,8

1.2.

Definition and diagnosis

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a minority of children with LGS, albeit not as a dominant

seizure type. When myoclonic seizures are predominant,
alternative diagnoses such as myoclonic astatic epilepsy (MAE
or Doose syndrome) should be considered.10 In MAE, the EEG is
expected to show generalized spike-and-wave activity at
frequencies of 3 Hz and above.11 However, some authorities
recognize a so-called myoclonic variant of LGS.

1.3.

Classification and causes

In the 1989 classification of epilepsies by the International

League Against Epilepsy (ILAE),12 LGS was included as
a generalized epilepsy. However, LGS can arise as a consequence of focal brain pathology and many children with LGS
have focal or multifocal seizures. Thus, LGS may be more
appropriately classified as an epileptic encephalopathy as
suggested in the ILAEs later Diagnostic Scheme.13

LGS is defined by three main criteria5,9:

1.3.1.
LGS

 Multiple seizure types, mainly generalized. These typically

include tonic and atonic seizures (often causing astatic
seizures drop attacks) and atypical absences. Other seizure
types that may occur include myoclonic seizures, generalized tonicclonic seizures and focal seizures. Tonic seizures
can occur during wakefulness but occurrence during sleep is
particularly characteristic. Approximately half of all patients
will have one or more episodes of nonconvulsive status
epilepticus (atypical absence, tonic, myoclonic or mixed).
 Abnormal electroencephalogram (EEG) with generalized
slow spike-and-wave discharges (SSW) at <2.5 Hz. These
occur during both wakefulness and sleep. In addition,
paroxysms of fast activity (rhythmic rapid spikes at 10
20 Hz) during sleep are also characteristic. Both patterns can
be interictal or ictal.
 Mental retardation or learning disabilities.

The majority of LGS cases (75%) have an identified underlying

cause and are designated as symptomatic.1Approximately
20% have a preceding history of West syndrome.5,14 LGS
without a history of West syndrome may occur in children
with conditions as diverse as cortical malformations or maldevelopments; neurocutaneous disorders (particularly
tuberous sclerosis); pre-, peri- and post-natal destructive
brain abnormalities (such as those caused by hypoxic
ischemic insults, infection or trauma); and, rarely, neurometabolic disorders.5 Although the brain abnormalities giving
rise to LGS are usually diffuse, they may be multifocal or even
focal. LGS due to focal brain abnormalities can occasionally be
treated successfully with lesionectomy.15
Many children with LGS have pre-existing diagnoses of
cerebral palsy, learning difficulties and/or behavioral problems. Furthermore, many will have had epileptic seizures
prior to the onset of LGS, even if they have no prior history of
West syndrome. In most cases, the underlying cause of LGS is
evident but, if not, it is appropriate to classify the childs
condition as probably symptomatic (synonymous with
cryptogenic).

Although authorities differ in their diagnostic inclusion and

exclusion criteria, all agree that a diagnosis of LGS requires the
presence of frequent seizures of at least two types and SSW on
EEG. Most also require seizures to be refractory to treatment
and/or evidence of cognitive deficits.5 In general, European
clinicians use stricter diagnostic criteria than those from North
America. Those employing the strictest criteria require LGS to
include tonic seizures and nocturnal fast rhythms.
The place of myoclonic seizures in LGS is controversial.
Most clinicians recognize that myoclonic seizures do occur in

1.3.2.

Symptomatic and probably symptomatic (cryptogenic)

Idiopathic LGS

In approximately 25% of cases, LGS occurs in a child with

previously normal psychomotor development and in whom
detailed investigations reveal no identifiable underlying cause.1,5
Such cases have traditionally been classified as cryptogenic.

european journal of paediatric neurology 13 (2009) 493504

However, this use of the term differs from that usually

employed in epileptology. In recent years, many authorities
have considered such cases as idiopathic. The role of genetic
factors in idiopathic LGS cases remains to be determined.

1.4.

What therapies are available to treat LGS?

Given the intractable nature of LGS, it is not surprising that

many different AEDs have been tried as treatments. However,
the evidence base as to which are the most appropriate therapeutic approaches is limited.
To identify treatments assessed in clinical trials in patients
with LGS, a Medline database search (limited to articles published in English) was conducted using the term LennoxGastaut combined with each of the following: acetazolamide,
benzodiazepine, bromide, carbamazepine, ethosuximide, felb
amate, lamotrigine, levetiracetam, phenobarbitone, phenytoin, primidone, rufinamide, sodium valproate, topiramate,
vigabatrin, zonisamide, immunoglobulin and steroids. Additional studies were identified through the Cochrane library
and from references cited in review articles. The results were
reviewed and classified as either double-blind, placebocontrolled clinical trials, or as uncontrolled studies.

2.1.

AEDs in LGS. Many studies are add-on trials in which patients

are taking 13 AEDs in addition to the test drug. These AEDs
vary between patients, making interpretation of the results
difficult. In addition, the criteria for patient inclusion vary
between trials and are often poorly described.18

Prognosis

The long-term prognosis for LGS is poor, in terms of both

seizure control and cognitive outcome. Up to 10% of children
with LGS die before reaching 11 years of age, some due to
injuries sustained during drop attacks.9 Most patients with
LGS will require assistance with some or all of their daily
activities for the rest of their lives6 while others may become
wheelchair dependent.16 However, a small proportion of
patients (about 5%) with otherwise typical LGS grow out of
their seizures in childhood or in their teenage years and
subsequently attain average or near average levels of ability.14
Seizures in patients with LGS may be relatively well
controlled on antiepileptic drug (AED) medication initially, but
resistance to drugs usually develops quickly. Ten years after
first diagnosis, seizures persist on a daily or weekly basis in
approximately two-thirds of patients.16 Around one-third of
idiopathic LGS cases and half of symptomatic cases lose the
characteristic SSW on EEG, usually in adult life, and are often
reclassified as having a non-specific, symptomatic generalized epilepsy, severe epilepsy with multiple independent
spike foci, or a focal epilepsy.16
Cognitive impairment increases with age in patients with
LGS, with significant decreases in IQ scores seen after 10
years.16 A retrospective case analysis in 101 patients identified
four independent risk factors for severe mental retardation in
LGS: nonconvulsive status epilepticus, previous diagnosis of
West syndrome, symptomatic etiology and an early age of
onset of epilepsy.17 These are probably also the most important prognostic criteria for seizure control and social outcome.

2.

495

Conventional antiepileptic drugs

Numerous AEDs have been and are used to treat LGS.

However, there are very few well-designed clinical trials of

2.1.1.
trials

Evidence from double-blind, placebo-controlled clinical

To date, there have been only five double-blind, placebocontrolled clinical trials investigating the effects of a single
therapeutic agent in LGS (Table 1).1924 These trials used
different designs and direct comparisons are difficult. There
have been no head-to-head trials of AEDs in LGS.
The first AED evaluated in a randomized, placebocontrolled, double-blind trial was cinromide (3-bromo-N-ethylcinnamamide).19 This 18-week study was conducted after
anecdotal reports and uncontrolled pilot studies suggested
that cinromide might help to reduce seizures in LGS and other
seizure disorders. However, no significant differences
between groups were found in seizure reduction or global
evaluation and cinromide is no longer studied or used in LGS.
However, the study did demonstrate an unexpectedly large
placebo response and highlighted the need for placebocontrolled trials in this population.
Felbamate
A dicarbamate with a broad spectrum of pharmacologic
activity,25 felbamate was evaluated in patients with LGS in
a 10-week, placebo-controlled, double-blind trial.20 Felbamate
treatment significantly decreased the frequencies of total
seizures and atonic seizures and was subsequently approved
by the FDA for use in LGS. It is available in a number of European countries and was also available in the UK for a short
period, until reports of fatal aplastic anemia and fatal hepatitis
led to its withdrawal shortly after it was given a license.26
Lamotrigine
Lamotrigine is a weak inhibitor of dihydrofolate reductase.27 Lamotrigine was evaluated in LGS in a 16-week,
randomized, double-blind, placebo-controlled trial.21 It
reduced the frequency of major seizures, with similar
reductions seen when drop attacks and tonicclonic seizures
were looked at individually. One-third of the lamotriginetreated group had a 50% reduction in the frequency of major
seizures. No difference between groups was seen in the
frequency of atypical absence seizures. Except for cold and
viral illnesses (which were more common in the treatment
group), there were no significant differences between groups
in adverse events. Lamotrigine is approved for the adjunctive
treatment of LGS in those who are 2 years of age or older.28
Topiramate
Topiramate is a sulphamate-substituted monosaccharide that
enhances GABA-mediated chloride influx.29 It was evaluated
in an 11-week, randomized, double-blind, placebo-controlled
trial,22 which showed that topiramate treatment was associated with significant benefits compared with placebo on the
frequency of drop attacks and on seizure severity (based on
parental global evaluation). The proportion of patients with
a 50% reduction in major seizures (drop attacks and

496

european journal of paediatric neurology 13 (2009) 493504

Table 1 Overview of published, double-blind, placebo-controlled trials of drug treatments for LGS.
Drug
Cinromide

Population
19

Felbamate20

LGS criteria

Key outcomes

n 73
Age 218 y
Taking 3 AEDs

History of multiple seizure

types with onset in
first decade
SSW on EEG
120 seizures in
6 weeks prior to baseline

Placebo or cinromide
(maximum of 83109
mg/kg/day) for 18 weeks

n 73
Age 436 y
Taking 2 AEDs

History of multiple
seizure types
SSW on EEG
180 seizures (atonic or
atypical absence) in 8
weeks prior to baseline

Placebo or felbamate
Felbamate vs placebo:
(maximum of 45 mg/kg/
day or 3600 mg/day
- Mean change in total seizure frequency:
[whichever was lower]) for
19% decrease vs 4% increase ( p 0.002)
70 days
- Mean change in atonic seizure frequency:
34% decrease vs 9% decrease ( p 0.01)
- Discontinuations due to adverse events: 1 vs 1

History of multiple seizure

types with onset in first
decade
Intellectual impairment
SSW on EEG
1 seizure every 2 days

Placebo or lamotrigine
(dose dependent on
concomitant valproate
usage and body weight)
for 16 weeks

Lamotrigine vs placebo:

Placebo or topiramate
(target dose w6 mg/kg/
day) for 11 weeks

Topiramate vs placebo:

Lamotrigine21 n 169
Age 325 y
Taking 2 AEDs

History of multiple
Topiramate22 n 98
Age 130 y
seizure types
Taking 1 or 2 AEDs SSW on EEG
60 seizures in month
prior to baseline

Rufinamide23

Interventions

n 138
Age 437 y
Taking 13 AEDs

Treatment-resistant
Placebo or rufinamide
seizures
(target dose 45 mg/kg/
SSW on EEG
day) for 84 days
90 seizures (including
drop attacks and atypical
absence seizures) in month
prior to baseline

Cinromide vs placebo:
- Response rate for total seizures: 27% vs 23%
- Discontinuations due to adverse
events: not reported

- Median change in major seizure frequency:

32% decrease vs 9% decrease ( p 0.002)
- Response rate for major seizures:
33% vs 16% ( p 0.01)
- Median change in drop attack frequency:
34% decrease vs 9% decrease ( p 0.01)
- Response rate for drop attacks:
37% vs 22% ( p 0.04)
- Discontinuations due to adverse events: 3 vs 7

- Median change in major seizure frequency:

26% decrease vs 5% increase ( p 0.015)
- Response rate for major seizures:
33% vs 8% ( p 0.002)
- Median change in drop attack frequency:
15% decrease vs 5% increase ( p 0.041)
- Response rate for drop attacks:
28% vs 14% ( p 0.071)
- Discontinuations due to adverse events: none

Rufinamide vs placebo:
- Median change in total seizure frequency:
33% decrease vs 12% decrease ( p 0.0015)
- Median change in tonicatonic
seizure frequency: 43% decrease
vs 1% increase ( p < 0.0001)
- Response rate for tonicatonic
seizures: 43% vs 17% ( p 0.0020)
- Discontinuations due to adverse events: 6 vs 0

Response is defined as 50% reduction in seizure frequency.

Cinromide and felbamate are not licensed in the UK; lamotrigine, topiramate and rufinamide are indicated for the treatment of Lennox-Gastaut
Syndrome.
AEDs, antiepileptic drugs; EEG, electroencephalogram; LGS, Lennox-Gastaut Syndrome; SSW, slow spike-and-wave discharge.

tonicclonic seizures) was significantly reduced by topiramate, although there was no apparent effect on absence
seizures. The most common adverse events were CNS-related
but did not result in any discontinuations. Topiramate is
approved for the adjunctive treatment of LGS in patients 2
years of age or older.28

Rufinamide
Rufinamide is a triazole derivative that is structurally unrelated to currently marketed antiepileptics. Its precise mode of
action is unknown, but it is thought to modulate the activity of
sodium channels, prolonging the inactive state of such
channels.30 Rufinamide has been evaluated in LGS in a

european journal of paediatric neurology 13 (2009) 493504

12-week randomized, placebo-controlled trial.23 It significantly reduced the frequencies of total seizures and drop
attacks, and significantly more patients in the rufinamide
group than in the placebo group achieved a 50% reduction in
drop attack frequency. The most common adverse events
were somnolence, nausea and fatigue. Rufinamide received
European approval in January 2007 as an adjunctive treatment
for LGS in patients 4 years of age or older.

2.1.2.

Evidence from uncontrolled studies

Numerous open-label, retrospective and observational studies

have investigated the efficacy of AEDs in LGS. Most of these
have small sample sizes, and/or include only a few patients
with LGS within a larger cohort. Adverse events are typically
not reported for the LGS subpopulation specifically. In addition, the criteria used to define LGS vary between studies,
making comparisons impossible.
Acetazolamide
Acetazolamide is licensed in the UK as an adjunct for treating
atypical absence, atonic and tonic seizures.28 However, no
published studies of acetazolamide in patients with LGS were
identified.
Benzodiazepines
The 1,4-benzodiazepines, which include clonazepam and
diazepam, are relatively old drugs that are approved for the
treatment of most forms of epilepsy. Although not evaluated
in controlled studies in patients with LGS, there is some
evidence that they can reduce the incidence of myoclonic
seizures in LGS.31,32 However, they are associated with
drowsiness, drooling, hyperactivity and ataxia,32,33 and some
have been shown to induce tonic seizures in patients with
LGS.34
Clobazam is a 1,5-benzodiazepine associated with a less
sedative effect than the 1,4-benzodiazepines and may be
particularly useful for managing tonic seizures.35 One openlabel study added clobazam to existing therapy in 31 children
with intractable epilepsy (14 with LGS) who had failed on at
least three AEDs.36 Although 25 children showed a >50%
reduction in seizures, three of the children with LGS still had
daily seizures. The most common adverse events were sedation, vomiting, irritability and behavioral changes. While clobazam appears to have a low potential for drugdrug
interactions, up to 40% of patients develop tolerance to the
drug.35 Clobazam is approved in Europe for the adjunctive
treatment of epilepsies in patients 3 years of age or older.27
Bromides
Bromides are still used by some clinicians to treat refractory
seizures, particularly in children.37 There have been two
studies of bromides that included patients with LGS. In a study
of 68 patients given unspecified doses of bromide, none of the
12 patients with LGS improved and four had an increase in
tonic seizures.38 In a study of 11 children (three with LGS)
given bromide therapy, six showed complete or significant
seizure control.39 While these trials reported minimal toxicity,
adverse events with bromides can be significant and even life

497

threatening. The most commonly seen problems are CNS

effects associated with high blood bromide levels (collectively
termed bromism). These include headache, drowsiness,
delirium, cutaneous effects and gastrointestinal effects.37
Bromides are not licensed for the treatment of epilepsy in
the UK.
Carbamazepine
Carbamazepine is licensed in Europe for the treatment of focal
and secondarily generalized tonicclonic seizures.28 The
benefits of carbamazepine have not been demonstrated in
controlled clinical trials in LGS. Studies have shown that carbamazepine can aggravate some generalized seizure types,
including absence, atonic, myoclonic and tonicclonic
seizures, and may also induce new-onset SSW on EEG.40
Ethosuximide
Ethosuximide, a succinamide, is approved in Europe for the
treatment of absence seizures. While its efficacy in LGS is
unproven in clinical trials, it is useful in controlling atypical
absence seizures.27 Ethosuximide may cause drowsiness,
headache and gastrointestinal upset.
Felbamate
In a 12-month, open-label follow-up to the randomized trial
described above,20 improvements achieved during the doubleblind phase were maintained during the follow-up period.41 Of
the patients who had previously received placebo, 62% achieved a >50% reduction in seizures within 1 month of starting
felbamate treatment. Overall, 50% of patients had a >50%
reduction in total seizures at 12 months. In a crossover study,
felbamate or placebo was given to 13 patients with LGS,
stabilized on sodium valproate, for two periods of 7 weeks.42
There appeared to be a synergistic effect between felbamate
and sodium valproate, with an overall reduction in the
frequency of total seizures and drop attacks. Further, felbamate treatment significantly reduced the frequencies of
astatic (atonic) seizures and generalized tonicclonic seizures
plus total seizure counts.43
Within 1 year of felbamates approval, reports of both
aplastic anemia and hepatic failure resulted in most patients
being withdrawn from the drug. It is still licensed in some
European countries, but is no longer licensed in many others,
such as the UK. The estimated incidence of aplastic anemia is
1 in 4785 to 1 in 37 037 felbamate-treated patients44 and
hepatotoxicity occurs in approximately 1 per 26 000 to 1 per
34 000 felbamate-treated patients. It should be noted that
a similar risk of hepatotoxicity is seen with sodium valproate.9
Lamotrigine
In addition to the one randomized, double-blind, placebocontrolled trial of lamotrigine in LGS described above,21
several small trials have shown the efficacy of lamotrigine as
an adjunctive therapy for reducing seizure frequency in LGS,
particularly against tonic, atonic and atypical absence
seizures.
In an open-label, add-on study of lamotrigine in 11 patients
with LGS,45 10 had a >50% decrease in seizure frequency. In

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european journal of paediatric neurology 13 (2009) 493504

a report involving 120 children with epilepsy,46 six of the 10

patients with LGS had a >50% decrease in seizures after
receiving lamotrigine adjunctive therapy for 3 months. In
a study of 50 children with intractable epilepsy who received
open-label lamotrigine, three of the eight patients with LGS
had a >50% decrease in seizures.47 In another open-label trial
in 93 patients with drug-resistant epilepsy,48 four of the nine
patients with LGS had a >50% reduction in seizures. In
a prospective, open-label study of 56 children with intractable
generalized epilepsy,49 11 of the 15 patients with LGS achieved
a 50% decrease in seizures when lamotrigine was given as
adjunctive therapy. In a retrospective, open-label, chart
review in 16 patients with LGS given adjunctive lamotrigine,50
eight had a >50% reduction in seizure frequency; the
frequency of tonic, atonic, tonicclonic and atypical absence
seizures, but not myoclonic seizures, was significantly
decreased. Lastly, in a double-blind, placebo-controlled
crossover trial in 30 children and adolescents with refractory
epilepsy (20 with LGS),51 there was a significant reduction in
seizure frequency during lamotrigine add-on therapy,
compared with placebo treatment. Adverse events described
with lamotrigine include sleep disturbances and rash.46,47,49,50
The latter is more likely to occur when used in combination
with sodium valproate. This combination may have a therapeutic interaction,52 but slow titration of lamotrigine when
being added to sodium valproate is essential to minimize the
risk of rash.
Levetiracetam
The efficacy and tolerability of levetiracetam in patients with
LGS has been evaluated in two studies and one case series,
with mixed results. In a 12-month, open-label, observational
trial, 35 children received levetiracetam as de novo monotherapy or add-on therapy; one of the two patients with LGS
showed a 50% reduction in seizures while the other had an
increase in seizures.53 An open-label pilot study evaluated
long-term levetiracetam use in 10 patients, four with LGS; two
patients experienced long-term seizure reductions, one had
an increase in seizure frequency, and one withdrew from
treatment.54 In a case series of six children with LGS treated
with add-on levetiracetam, 100% reductions in myoclonic and
tonicclonic seizures were seen in four patients.55 Levetiracetam is licensed in Europe for the treatment of partial
seizures with or without secondary generalization in patients
4 years of age or older.28
Phenobarbitone
Despite being the earliest developed anticonvulsant still in use
worldwide and licensed for all seizure types except absence
seizures,28 phenobarbitone does not appear to have been
studied in patients with LGS.
Phenytoin
Phenytoin is licensed in Europe for the treatment of all forms
of epilepsy except absence seizures.28 However, it has not
been evaluated in patients with LGS in clinical trials.
Primidone
Primidone was originally licensed in 1954 and is currently
indicated for all forms of epilepsy except absence seizures.28

No published studies of primidone in patients with LGS were

identified.
Rufinamide
An open-label extension of the randomized study described
above23 included 124 patients receiving rufinamide for
a median of 432 days. The initial reduction in total seizure
frequency (43% at 6 months) was maintained, with further
improvements seen over 3 years.56 The most common adverse
events were somnolence, pyrexia and vomiting.56 While drug
drug interactions are minimal between rufinamide and most
other antiepileptic drugs, sodium valproate may increase
levels of rufinamide in children by up to 70%.30
Sodium valproate
Although sodium valproate has not been evaluated in
randomized clinical trials in LGS, it is indicated for all forms of
epilepsy.28 A noncontrolled study of sodium valproate in
children and adolescents with a variety of generalized
seizures often seen in LGS demonstrated that it was effective
at reducing the frequency of seizures and in many cases the
use of concomitant AEDs.28 Sodium valproate is usually the
drug of choice for epilepsies associated with generalized SSW
discharges, myoclonic epilepsies and absences.9,57 Anorexia
and gastrointestinal upset are the most commonly reported
adverse events in young children.58 Sodium valproate is also
associated with a risk of hepatic failure and pancreatitis.
Topiramate
In an open-label extension of the randomized, double-blind,
placebo-controlled trial described above,22 97 patients
continued taking topiramate and other concomitant AEDs.59
After 6 months of receiving topiramate, 4568% of patients
showed a 50% reduction in total seizures, drop attacks,
atypical absence seizures, myoclonic seizures and tonic
clonic seizures.
Other topiramate trials have typically been open-label,
add-on studies in children with intractable epilepsy, including
a few with LGS. Four such studies are briefly described here. In
a long-term, open-label pilot study in 18 patients with LGS
receiving topiramate as add-on therapy,60 six of the eight
patients still receiving topiramate had a >50% reduction in
seizure frequency, with the best results seen in drop attacks,
atypical absence seizures and generalized tonicclonic
seizures. Similarly, in a prospective, open-label, add-on study
in 45 patients with LGS,61 topiramate treatment was associated with a >50% reduction in seizures in 18 patients after an
average treatment period of 15.8 months; it was most effective
at reducing the incidence of drop attacks and tonicclonic
seizures. In another add-on trial,62 47 children (25 with LGS)
received topiramate and 60% of children had a >50% reduction
in seizures after at least 6 months of treatment; there was no
difference in efficacy between different epilepsy diagnoses.
Lastly, in contrast to the results described above, a long-term,
retrospective, open-label add-on study in 277 children with
drug-resistant epilepsy, who received topiramate for a mean
period of 27.5 months,63 showed only two of the 15 children
with LGS had a >50% reduction in seizures. A complete loss of
efficacy was seen in the patients with LGS by 30 months.

european journal of paediatric neurology 13 (2009) 493504

The most commonly reported adverse events with topiramate include infection, somnolence, drowsiness, nervousness, anorexia and weight loss.59,6163 Topiramate has been
associated with difficulties in language processing and
therefore requires a slow dose titration schedule.
Vigabatrin
The antiepileptic effects of vigabatrin in children have been
demonstrated in three studies, although the numbers of
patients with LGS included were small. In the earliest study,64
vigabatrin was administered as add-on therapy in an openlabel, uncontrolled trial of 135 children with refractory
epilepsy; half of the 26 patients with LGS showed some
reduction in seizure frequency. In a 16-week single-blind trial
in 61 children with refractory epilepsy who received add-on
vigabatrin,65 two of the seven patients with LGS experienced
a >50% decrease in seizure frequency, but four experienced
a >50% increase in seizure frequency. In an open-label, doseranging study in 20 children with LGS, vigabatrin was added to
first-line valproate therapy that was not adequately controlling seizures.66 After titrating to either 4000 mg/day, the
maximum tolerated dose, or the dose that controlled seizures,
patients were maintained for 12 months. During this time,
eight patients became seizure-free and nine had a >50%
reduction in seizure frequency. Vigabatrin can exacerbate
generalized seizures. Nevertheless, it is a first-line drug for the
treatment of infantile spasms and it is licensed as a monotherapy for their management in some European countries.27
The most commonly reported adverse events with vigabatrin are weight gain and agitation.6466 Since it was
licensed in the UK, visual field defects resulting in the development of tunnel vision have been reported in adults and
children receiving vigabatrin,67 resulting in its restricted use.27
Zonisamide
Zonisamide is indicated as an adjunctive therapy for refractory
partial seizures with or without secondary generalization, but is
not recommended for use in patients under 18 years of age.27 A
long-term postmarketing survey involving 1631 patients in
Japan indicated that 28% of those with West syndrome or LGS
improved after treatment with zonisamide.68

2.2.

Other drug treatments

2.2.1.

Corticosteroids

Corticosteroids, such as prednisolone and adrenocorticotropic

hormone (ACTH), have been used to treat epilepsies for over
50 years.69 Several small uncontrolled studies have investigated these compounds in LGS. In 45 children with LGS who
received ACTH,70 23 became seizure-free for >10 days,
although 10 subsequently relapsed within 6 months. In
a small trial in 23 children treated with ACTH for 2 weeks,71 six
of the seven patients with LGS showed an improvement in
seizure control, EEG pattern and behavior. In a study of 28
children treated with prednisone for 12 weeks,72 seven of the
10 patients with LGS achieved seizure freedom. Based on the
limited studies of steroids in LGS, it is unclear which seizure
types respond best to treatment. The use of corticosteroids in
epilepsy is complicated by the many preparations available

499

and by a lack of agreement as to which dose or treatment

regimen is most effective. Corticosteroids (prednisolone and
tetracosactide, the synthetic analogue of ACTH) are not
specifically licensed for the treatment of epilepsies in the
UK,27 and their use in LGS would typically be in combination
with AEDs.69 Given their long-term adverse effects,
corticosteroids are mainly used in LGS to treat episodes of
nonconvulsive status epilepticus not responding to
conventional AEDs.

2.2.2.

Intravenous immunoglobulin

Intravenous g-globulin therapy (IVIG) is used to treat a variety

of disorders. Treatment for chronic conditions typically
involves high-dose infusions administered every few weeks.
Anecdotal evidence of improvements in both seizures and
behavior in patients with epilepsy receiving IVIG for allergies
led to trials being conducted. These have typically been small
and, due to the nature of the treatment, often not placebocontrolled. However, reports of IVIG use in LGS are mixed. In
one trial of nine patients (eight with LGS),73 four children
showed complete remission and three showed a >50%
reduction in seizures. In three patients, improvement was
evident after the first injection. Remission lasted for the entire
follow-up period of 2226 months in three patients. Two other
trials of IVIG in LGS, one in 10 patients74 and another in seven
patients,75 have reported similar benefits on seizure reduction. Although not licensed for the treatment of LGS in the UK,
IVIG is well tolerated, and can be administered as adjunctive
therapy as it does not alter the plasma levels of AEDs.73
However, IVIG is costly and administration inconvenient, and
it is usually reserved for use in children not responding to
other treatments.

2.3.

Nonpharmacologic interventions

Nonpharmacologic treatments for LGS include the ketogenic

diet and surgical procedures corpus callosotomy and vagus
nerve stimulation (VNS). These approaches have typically
been tried only after pharmacologic treatment has failed.

2.3.1.

Ketogenic diet

The ketogenic diet was developed in the 1920s to mimic the

observed benefits of fasting on seizure control. It comprises
a high-fat, low-carbohydrate, low-protein diet. The effectiveness of the ketogenic diet has only recently been shown in
a placebo-controlled study.76 A meta-analysis pooling data
from 19 observational studies of children with epilepsy
(n 1084) indicated that the ketogenic diet is effective in
reducing the number of seizures. The odds ratio of treatment
success (>50% seizure reduction) among children remaining
on the diet relative to those discontinuing was 2.25 (95%
confidence interval 1.692.98).77 It is claimed to be particularly
effective in LGS.78 While effective, the diet can be difficult to
maintain and there have been no long-term studies of its
efficacy. Adverse events include renal stones, hyperuricemia
and acidosis.79

2.3.2.

Corpus callosotomy

The corpus callosum is involved in the propagation of electrical discharges from one hemisphere to another, and in the

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european journal of paediatric neurology 13 (2009) 493504

generation of secondary generalized seizures.80 Surgical

disconnection of the cerebral hemispheres (corpus callosotomy) has evolved since the 1940s. Today, the procedure is
often limited initially to the anterior portion of the corpus
callosum.80 Completion of the callosal division can be performed if seizures persist.76 The procedure has been used to
treat several drug-resistant childhood epilepsies, including
LGS.80 Drop attacks appear to be the most responsive seizure
type.81 As many as 80% of patients with LGS will show a >50%
reduction in seizures following corpus callosotomy.82
However, only half of patients maintain a >50% reduction in
seizure frequency for 27 years, suggesting that seizure
control may be transient.80 Complications of callosotomy can
include cerebral infarction, hydrocephalus, transient mutism
and the disconnection syndrome.

2.3.3.

Vagus nerve stimulation (VNS)

The efficacy of vagus nerve stimulation (VNS) is well established in adults and adolescents with partial epilepsy. In
several small studies that included patients with LGS, 3773%
of patients had a >50% decrease in seizures.82 A retrospective
database analysis of 552 patients with LGS evaluated the
response to VNS in patients who were nave to surgery vs
those who had already had a callosotomy. In patients with no
prior surgery (n 483), a >50% reduction in overall seizures
was seen in 50% of patients at 3 months and 55% of patients at
18 months. Results were similar in the patients who had
a prior callosotomy (n 69).82 There is no information available about which seizure types respond best to VNS.82
Common adverse events include bleeding and infection from
the surgery, and hoarseness and cough during stimulation.82

3.

How should LGS be treated?

3.1.

Review prior and existing medication

It is rare for the clinician to make a diagnosis of LGS in a drugnave patient. Usually the syndrome has either evolved from
West syndrome or from a non-specific seizure disorder that
later develops the characteristic features of LGS. Once the
diagnosis has been made, the clinician should first review
previous and current AEDs. This should determine which, if
any, AEDs suitable to treat LGS have been tried already and
whether the child is on any AEDs, such as carbamazepine,
which could exacerbate LGS.
It should be noted that drugs that have been tried before
may have failed prior to the development of LGS, and it may be
appropriate to consider their use again. The adage first do no
harm is especially relevant. Tolerance to medications in
patients with LGS is very common and a combination of drugs
is usually required to reduce the incidence of seizures.
Consequently, the potential for children with LGS to be treated
with multiple AEDs is very high and the adverse effects of
these may be worse than the disorder itself. For example,
drowsiness (whether natural or drug-induced) in LGS is often
associated with increased seizures and so avoiding sedation is
important. As with any epilepsy, the initial aim should be for
monotherapy. However, most children with LGS are probably
better controlled on two AEDs, and a few children may benefit

from three AEDs. It is probably never justified to maintain

a child with LGS on four or more AEDs.

3.2.

Develop treatment goals

The next step is to develop goals for treatment. Initially, it is

reasonable to aim for complete seizure freedom. However, in the
majority of children with LGS it will quickly become clear that
this is an unrealistic goal. The clinician, in consultation with the
family, must then decide on an individual basis what the aim of
treatment is to be. This will require periodic review. In most
cases specific aims will be built around the desirability of maximizing social functioning whilst minimizing adverse drug
events. Examples of appropriate therapeutic aims in LGS include:
 Minimizing the number of drop attacks.
 Minimizing the number of daytime seizures, so allowing the
child to attend school.
 Preventing and/or quickly treating prolonged convulsive
seizures.
 Preventing and/or quickly treating episodes of nonconvulsive status epilepticus.

3.3.

Introduce treatment interventions

A suggested algorithm for treating LGS is shown in Fig. 1.

Although the use of sodium valproate for LGS has not been
assessed in any randomized controlled studies, it is the initial
choice of most clinicians and there is no reason to recommend
any change to this practice. Provided there is careful monitoring for adverse effects, the clinician should be prepared to
use higher doses (up to 40 mg/kg/day) than might be considered for other, less severe, epilepsies.
If the therapeutic goal is not achieved with sodium valproate, there is no consensus as to which is the next most
appropriate AED to administer. The most recent UK NICE
guidelines list valproate, lamotrigine and topiramate as firstline options for treating LGS, with clobazam, clonazepam,
ethosuximide and levetiracetam recommended as second-line
options.83 However, none of these second-line options are
specifically licensed for LGS,27 and no details are listed for
treatment goals, using monotherapy vs add-on therapy, or
nonpharmacologic interventions.83 The American Academy of
Neurology guidelines recommend broad-spectrum AEDs and
recognize that lamotrigine and topiramate appear to be effective for treating LGS.84 A 2003 Cochrane review concluded that
the optimum treatment for LGS remains uncertain, with no
study demonstrating any one drug to be highly efficacious.18 It
would seem logical to consider one of the agents whose efficacy
has been shown in double-blind, placebo-controlled studies,
i.e., felbamate (not licensed in the UK), lamotrigine, topiramate
and rufinamide. However, the potentially fatal toxicity of felbamate constitutes a strong argument against using it at this
stage, whilst clinical experience with rufinamide is still very
limited. Individual aspects of the childs condition may suggest
one agent to be more or less appropriate. For example, if
myoclonic seizures were prominent then lamotrigine might
not be a good choice, since it exacerbates seizures in some
myoclonic epilepsies.85,86 In a child whose weight gain was

european journal of paediatric neurology 13 (2009) 493504

Fig. 1 Recommended Lennox-Gastaut Syndrome

treatment algorithma.
a
All drugs except bromides and felbamate are licensed for
the treatment of LGS and/or partial and/or generalized
seizure types. Zonisamide is not recommended for use in
patients under 18 years of age.
b
Benzodiazepines can be considered as second-line agents
for Lennox-Gastaut Syndrome (although not specifically
indicated as such), but it may be better to use them in short
courses to treat convulsive and nonconvulsive status
epilepticus and to break cycles of very poor seizure
control.

501

suboptimal, topiramate would be best avoided, but conversely

would be a good choice if the child was overweight. Neither
levetiracetam nor zonisamide have been assessed in
randomized, controlled studies in LGS but since they are broadspectrum agents it is probable that they are effective in LGS.
Thus, although not specifically approved for the treatment of
LGS, they can be considered as second-line agents.
Achieving good seizure control in LGS with monotherapy is
unlikely and therefore the second-line agent is best added to
the sodium valproate (making any appropriate adjustments
for AED interactions). If the response to the new agent is
dramatic, the sodium valproate can subsequently be withdrawn. In many children with LGS, good seizure control will
not be obtained after the initial second-line agent and it is
then appropriate to trial other second-line agents. However, it
is at this point that great care must be taken to avoid excessive
polypharmacy. This can be achieved by choosing which
background AED to continue treatment with and, as each
new agent is tried, the other second-line agent can be withdrawn. This will mean that the child is only treated with three
AEDs for relatively short periods. In most cases, sodium valproate will provide the most suitable background AED.
However, other drugs can act as the background AED if they
appear to be superior to sodium valproate.
Benzodiazepines can also reasonably be considered as
second-line agents for LGS (although not specifically licensed
as such). However, they are generally the most useful agents
for treating convulsive and nonconvulsive status epilepticus
(although they can precipitate tonic status) and can also be
used to break cycles of very poor seizure control. Therefore, it
is better to avoid their regular use and save them for short
courses to treat these problems. However, the clinician must
be pragmatic: if a benzodiazepine is introduced with a view to
being used only short-term, but the response is dramatic and
sustained, it would be inappropriate to discontinue treatment.
The two main nonpharmacologic treatments to consider
are the ketogenic diet and VNS. Clinical experience suggests
that, in LGS, the ketogenic diet is more likely to achieve
complete or near-complete seizure control than VNS and on
this basis should probably be preferred. However, maintaining
the required diet is very demanding on the patients carers
and, for this reason, treatment is not suitable for all children
with LGS. Given the evidence of efficacy of the ketogenic diet, it
should be offered at a relatively early stage, probably after one
or two of the second-line AEDs have failed. It should be noted
that there is a risk of severe acidosis with topiramate and its
use in combination with the ketogenic diet is best avoided.
After one or more of the nonpharmacologic treatments
have been unsuccessful, the remaining second-line agents
should be tried. If these have all failed, third-line agents can be
considered (see Fig. 1). However, some of these, notably vigabatrin, phenytoin and carbamazepine, can (or probably can)
exacerbate seizures in patients with LGS and their use must be
very carefully monitored. Refractory status is sometimes
treated with steroids. There is no evidence that steroids or
immunoglobulin infusions offer a long-term solution in LGS.
The usual pattern seen in LGS is for successive new AEDs to
have a beneficial effect in terms of reducing seizures.
However, this benefit is often not sustained and after some
weeks or months seizure control deteriorates once again.

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european journal of paediatric neurology 13 (2009) 493504

Some children with LGS do not appear to show any worthwhile response to successive AEDs. These children may be
better coming off all AEDs, rather than being submitted to
endless trials of worthless medication.
The clinician treating a child with LGS must be pragmatic.
Although the advice given above is suitable for most children
with LGS, individual circumstances may suggest alternative
approaches. Examples of this are:
 Focal brain pathology. If the LGS is secondary to focal brain
pathology and/or includes focal seizures, it may be appropriate to try drugs active against focal seizures, such as
carbamazepine, at a relatively early stage.
 Tuberous sclerosis. Seizures in children with tuberous
sclerosis often respond very well to vigabatrin. Notwithstanding concern about irreversible visual field defects, this
drug should be considered early, possibly first-line, in children with LGS caused by tuberous sclerosis.
 Polymicrogyria. Anecdotal evidence suggests that ethosuximide is often successful against seizures caused by polymicrogyria. Therefore, it should be tried early in such cases.
 remedial brain pathology. In the very rare cases where LGS
occurs in association with surgically remediable brain
pathology (e.g., old middle cerebral artery infarcts) early
referral for resective surgery should be made.
 Continued drop attacks. In cases where frequent tonic or
atonic drop attacks continue, callosotomy may be considered, although any benefit may be temporary.

4.

Conclusions

The evidence supporting the use of available treatments for

LGS is not robust. There is a need for new treatments to be
developed and for these and current treatments to be tested in
LGS in controlled clinical trials. However, in some cases,
patients with LGS can be successfully treated with current
therapies and it is important to avoid being unduly pessimistic. Following the suggested algorithm should allow many
patients with LGS to achieve their treatment goals while
minimizing adverse events and polypharmacy.

Acknowledgements
The authors thank Rebecca Sutch, PhD (Envision Pharma,
Horsham, UK) for editorial assistance with the preparation of
the manuscript. Editorial assistance was funded by Eisai Ltd.
Potential conflicts of interest: Dr Ferrie has received honoraria
from Eisai, UCB, Janssen Cilag and Medtronic. Dr Amit Patel is
an employee of Eisai Ltd.

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