Review
Lennox-Gastaut syndrome: a consensus approach on
Lancet Neurol 2009; 8: 82–93
Institute for Children and
Adolescents with Epilepsy–
IDEE, University Hospitals of
Lyon and INSERM U821, Lyon,
France (A Arzimanoglou MD);
NYU Comprehensive Epilepsy
Center, New York, USA
(J French MD); Department of
Clinical Neurological Sciences,
Epilepsy and Clinical
Neurophysiology, London
Health Sciences Centre–
University Campus, London,
Ontario, Canada
(W T Blume MD); University
College London–Institute of
Child Health, London, UK
(J H Cross MD); Epilepsieklinik
für Kinder und Jugendliche
Epilepsiezentrum Kork, Kehl,
Germany (J-P Ernst MD);
Department of Pediatrics,
Epilepsy Service and EEG
Laboratory, Medical University
of Vienna, Vienna, Austria
(M Feucht MD); Centre Saint
Paul, Hôpital Henri Gastaut,
Marseille, France
(P Genton MD); Pediatric
Neurology Unit, Children’s
Hospital A Meyer, University of
Firenze, Italy (R Guerrini MD);
Leitender Arzt, Klinik für
Neuropädiatrie und
Neurologische Rehabilitation,
Epilepsiezentrum für Kinder
und Jugendliche, Vogtareuth,
Germany (G Kluger MD);
Epilepsy Institute of Virginia,
Department of Neurology,
Virginia Commonwealth
University of Richmond, USA
(J M Pellock MD); Institute of
Neurology IRCCS C Mondino
Foundation and Clinical
Pharmacology Unit, University
of Pavia, Pavia, Italy
(E Perucca MD); and University
of Tennessee Health Science
Center, Memphis, USA
(J W Wheless MD)
Correspondence to:
Alexis Arzimanoglou, Sleep and
Paediatric Neurophysiology
Department and Institute for
Children and Adolescents with
Epilepsy–IDEE, HFME, University
Hospitals of Lyon, 59 Boulevard
Pinel, 69677, Bron, France
alexis.arzimanoglou@chu-
lyon.fr
82
diagnosis, assessment, management, and trial methodology
Alexis Arzimanoglou, Jacqueline French, Warren T Blume, J Helen Cross, Jan-Peter Ernst, Martha Feucht, Pierre Genton, Renzo Guerrini,
Gerhard Kluger, John M Pellock, Emilio Perucca, James W Wheless
Lennox-Gastaut syndrome is one of the most severe epileptic encephalopathies of childhood onset. The cause of this
syndrome can be symptomatic (ie, secondary to an underlying brain disorder) or cryptogenic (ie, has no known cause).
Although Lennox-Gastaut syndrome is commonly characterised by a triad of signs, which include multiple seizure
types, slow spike-wave complexes on electroencephalographic (EEG) recordings, and impairment of cognitive function,
there is debate with regard to the precise limits, cause, and diagnosis of the syndrome. Tonic seizures, which are
thought to be a characteristic sign of Lennox-Gastaut syndrome, are not present at onset and the EEG features are not
pathognomonic of the disorder. There are few effective treatment options for the multiple seizures and comorbidities,
and the long-term outlook is poor for most patients. Probably as a result of the complexity of the disorder, only a few
randomised trials have studied Lennox-Gastaut syndrome, and thus many of the drugs that are more commonly used
have little or no supporting evidence base from controlled trials. In this Review, we discuss the main issues with
regard to the diagnosis and treatment options available. We also suggest key considerations for future trials and
highlight the importance of a comprehensive approach to the assessment and management of this syndrome.
Introduction Characterisation of LGS
Lennox-Gastaut syndrome (LGS) is a severe form of History
epilepsy with childhood onset. LGS can occur as a The electroclinical syndrome was identified by the
secondary result of an insult to the brain either during the Marseille School in France in 1966,1 after the medical thesis
prenatal, perinatal, or neonatal periods, or can occur in an of Dravet2 and the publications of Gastaut and co-workers3
otherwise previously healthy child. Seizures associated and Sorel.4 Gastaut and co-workers1 suggested the term
with LGS might occur de novo or might follow severe “Lennox syndrome” to describe an epileptic encephalopathy
infantile seizure disorders, such as infantile spasms. LGS that had a childhood onset, diffuse slow spike-wave
is associated with many types of seizures (including tonic, complexes, and several types of seizures (including tonic
atonic, and atypical absences), moderate to severe seizures), as had been first reported by Lennox and Davis.5
cognitive dysfunction, and the persistence of seizures into The term “Lennox-Gastaut syndrome” was introduced
adulthood. In addition to concerns about social integration later6 and gained wide acceptance, even though the criteria
and care, LGS is one of the most complex epileptic for the definition of this disorder have since been modified.
disorders to manage, both for the general or paediatric The syndrome was further delineated between 1966 and
neurologist and for specialists in epilepsy. 1972 and a definition of LGS was proposed by Beaumanoir7
The cause, history, types of seizures that progressively and adopted by the International League Against Epilepsy
enrich the clinical picture, and specific electroencephalo- Classification Commission in 1989.8
graphic (EEG) features are not pathognomonic for LGS,
which makes a diagnosis difficult, particularly at onset. Problems with the definition
There is no biological marker of LGS available as yet The term LGS is often loosely used to denote severe
and the many causes that are associated with the epilepsy syndromes of childhood featuring several types
syndrome complicate the assessment of the disorder of intractable seizures, including falls. However, such a
and the treatment protocols for trials. More than ten broad definition encompasses several types of epilepsy,
new antiepileptic drugs have been recently developed including some of the epilepsy disorders that have
and might improve outcomes for patients with LGS; predominantly myoclonic-astatic seizures, for which the
however, these various options make treatment choices outcome and therapy can differ.9
difficult. The nosological uncertainty is accentuated by the fact
In this Review, we describe the main electroclinical that the core seizures (ie, tonic, atonic, and atypical
features of LGS, discuss several topics that are still absences) are not always present at onset and the
debated with regard to the definition of the syndrome, interictal EEG pattern of slow spike-waves that is
compare data that are available from drug trials, and associated with LGS is not pathognomonic. In addition
present a consensual approach for optimum global to the types of seizures that are more commonly
management of the disorder. There is a need for further associated with the syndrome, other types of seizures
trials and new drugs for the early treatment of LGS to (eg, focal or myoclonic) and other EEG features can occur.
be unanimously accepted by the epilepsy community. A substantial proportion of cases evade precise
We emphasise some of the issues that, in our view, classification and the differentiation lies upon the
would improve the design of such further trials. quantitative proportions of the various types of seizures
www.thelancet.com/neurology Vol 8 January 2009

and EEG interictal abnormalities rather than on the
specific features.9 Studies on the prognosis of patients
with LGS, the inclusion criteria for drug trials, and the
results obtained usually indicate the above-mentioned
nosological uncertainties. Another factor that needs to be
taken into account is aetiological heterogeneity. Given
the poor prognosis of this syndrome for seizure control
and cognitive development, the term LGS should be
applied with caution. The distinction of obligate clinical
and EEG features from associative features helps to
distinguish LGS from other epilepsy disorders that have
different prognoses.
Identification of the syndrome
The classic LGS triad, when the syndrome is fully
developed, comprises many types of seizures that include
tonic seizures, mental retardation, and an interictal EEG
pattern of diffuse, slow spike-wave complexes (panel 1).
Some authors7 consider the presence of fast (10 Hz)
rhythms that are associated with the tonic attacks or that
occur with minimal manifestations, particularly during
non-REM sleep, an essential criterion. The diagnosis of
LGS is dependent on the interaction between the clinical
features and the EEG features.
Seizure types
Tonic seizures
Tonic seizures are the most characteristic type of seizure
in LGS1,10 and their presence is a prerequisite for the
diagnosis of this syndrome. However, the reported
occurrence of this type of seizure varies: a higher incidence
has been found in published series of patients in whom
recordings of sleep were systematically obtained. Tonic
seizures are not necessarily present at the onset of LGS
and the age of the patient at inclusion in a series could be
another factor that might explain these variations in
occurrences. Tonic refers to “a sustained increase in
muscle contraction lasting a few seconds to minutes”.11
This might be limited to a flexor movement of the head
and trunk with apnoea occasionally preceded by a brief cry
(axial subtype) that is associated with abduction and
elevation of the limbs, which usually involves the arms
with clenching of fists (axorhizomelic); or might affect
most muscles (global tonic attacks) and the distal parts of
the limbs.12 Grimacing and transient truncal and proximal
limb stiffening can be subtle. When the patient is standing,
the flexion of the lower limbs and axis can forcefully throw
the patient to the ground, which further complicates
differential diagnosis with atonic (or even myoclonic)
seizures. There are also subtle variations in tonic seizures
that only comprise, for example, a slow rolling upward of
the eyes. In these cases, the use of polygraphy, including
surface electromyography recording, is particularly useful.
Atypical absences
Atypical absences1,10 are the second most common type of
seizures. This is a term used for any seizure that has a
www.thelancet.com/neurology Vol 8 January 2009
Review
Panel 1: Summary of electroclinical features and progression of LGS
Onset
• Usually before the age of 8 years. Occurrence rates peak between 3 and 5 years of age,
although late cases in early adulthood have been reported
• In young children with no obvious recognised cause (ie, cryptogenic), LGS usually
begins with episodes of drop attacks, followed by other types of seizures
• The full clinical picture can also gradually develop after infantile spasms and West
syndrome
• Interrictal EEG when the patient is awake is usually abnormal from the onset of the
syndrome. Reactivity of background rhythms might be conserved; these rhythms are
usually slow and poorly organised for the age of the child. EEG patterns when asleep
can be normal at this stage
• Cause is heterogeneous. Brain damage (focal or multifocal abnormalities of cortical
development, tuberous sclerosis, and, less commonly, acquired destructive lesions or
metabolic diseases) plays a major role, whereas genetic factors are regarded to be less
important
• Neurological symptoms can be absent, depending on the underlying cause
• Psychomotor development at the time of first seizures seems normal or the child
might present with a homogeneous delay in development (of varying degrees) with
or without signs of a personality disorder
State period*
• Several seizure types: tonic seizure is the characteristic, prerequisite type of seizure
associated with LGS; atypical absences are associated with a decrease in consciousness;
atonic or astatic types are characterised by abrupt falls and are usually associated with
a loss of consciousness; other seizure types that might occur include myoclonic,
partial, or generalised tonic-clonic, although these are seen less frequently
• Episodes of non-convulsive status: these episodes are commonly characterised by the
alternation of tonic attacks and episodes of confused behaviour, frequently with erratic
myoclonic activity of the face and upper limbs, which can last for hours to weeks
• Characteristic EEG abnormalities: these abnormalities are bursts of diffuse slow spike-
waves at 2–2·5 cycles/s in the interictal EEG when the patient is awake or bursts of fast
rhythmic waves and slow polyspikes and generalised fast rhythms at about 10 cycles/s
during sleep
• Developmental delay: this delay increases with time, with a clear loss of skills and,
often, with the presence of psychotic symptoms
Evolution
• LGS is a chronic disorder. Epilepsy, although less active, remains untreatable. The
intellectual and psychological deficits tend to worsen
• The EEG recording when the patient is awake remains replete with slow spike-waves
and the EEG recording when asleep with rapid rhythms
EEG=electroencephalogram. LGS=Lennox-Gastaut syndrome. *The clinical picture remains relatively stable in comparison to
the onset period.
principal clinical manifestation of a brief loss or lapse of
consciousness. These seizures are difficult to identify
because of their gradual onset and termination in patients
whose diminished cognitive abilities might already limit
their responsiveness.
Seizures with a different underlying pathophysiology
can manifest clinically as a “pseudo absence”, including
complex partial seizures, seizures associated with
generalised spike-waves on EEG, and seizures with other
EEG characteristics that make them difficult to classify.13,14
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 Review
A common occurrence of atypical absences and the many
other types of seizures seen in patients with LGS might
indicate widespread brain pathology.
Sudden tonic or atonic falls
Sudden tonic or atonic falls (“drop attacks”) are
particularly hazardous and occur in about 56% of patients
who have slow spike-waves.10 However, drop attacks,
usually preceded by a brief myoclonic jerk, are also
observed in other epilepsy syndromes (eg, in epilepsies
with predominantly myoclonic-astatic seizures) that do
not necessarily evolve to LGS. Therefore, the presence of
drop attacks is not diagnostic for LGS.
Non-convulsive status epilepticus
Between 50% and 75% of patients with LGS have episodes
of non-convulsive status epilepticus, which usually
consist of subcontinuous atypical absences with varying
degrees of altered consciousness that are periodically
interrupted by recurring brief tonic seizures.9
Myoclonic seizures
Myoclonic seizures occur in many generalised epilepsy
syndromes and should be thought of as associated features
but not as defining features.9 These seizures are shorter
(<100 ms) than tonic events11 but can also lead to falls.
Other types of seizures
In addition to the core seizures of LGS, other types of
attacks (eg, focal seizures with or without secondary
generalisation, tonic-clonic generalised seizures, and
unilateral clonic seizures) are common. These types of
EOG
L Delt
Fz–Cz
PNO
100 μV
1s
Figure 1: EEG recording from a 12-year-old girl with bilateral perisylvian polymicrogyria and LGS
Tonic seizure recorded during sleep. Interictal generalised slow spike-wave and wave discharges precede a tonic
seizure, which is characterised electrographically by high-amplitude fast rhythms that last about 10 s. During the
ictal discharge, a progressive tonic contraction becomes apparent in the recorded muscle (L Delt) and an apnoea is
visible in the respirogram (PNO). The ictal discharge is followed by slow waves and generalised polyspike and wave
complexes. EEG=electroencephalogram. EOG=electro-oculograph. Fz–Cz=fronto–central midline EEG recording.
L Delt=left deltoid. LGS=Lennox-Gastaut syndrome. PNO=recording of respiration.
84
seizures usually occur in the later stages of LGS but can
sometimes precede the core attacks, which further
complicates differential diagnosis.
Learning disabilities
A variable degree of learning disability is another important
component of the classic LGS triad. A small proportion of
children (10–20%) are within the accepted limits of
normality but usually have difficulties in everyday life that
seem to be caused by a slowing of mental processing.
Many patients (20–60%) already have delayed development
at onset of LGS15 and there are neurological signs or
abnormalities in neuroimaging that are usually associated
with this syndrome (secondary or symptomatic cases). In
cryptogenic cases (30%), the development of the child
seems normal before the appearance of the first seizures.
The proportion of patients who have cognitive impairments
increases to 75–95% by 5 years from onset of the
syndrome.16,17 The deterioration is self-limited and is not
associated with the appearance of other neurological signs
and symptoms. There have been few longitudinal
neuropsychological studies and those done usually have
poor statistical power. However, the epileptic activity is
likely to play a part in the mechanism of the difficulties in
cognition and behaviour. Psychiatric disorders and
behavioural disturbances might also be associated with the
global epilepsy syndrome (ie, LGS).
EEG features
The classic EEG feature of LGS—the slow spike-wave
pattern that was originally known as the petit mal
variant—consists of a spike (duration <70 ms) or a sharp
wave (70–200 ms), followed first by a positive deep
“trough” and then by a negative wave (350–400 ms). These
bilaterally synchronous complexes repeat at 1–2 Hz. In
prolonged paroxysmal discharges, slow spike-waves
usually occur in a larger proportion than the 3 Hz spike-
waves seen during recordings while awake or in non-
rapid-eye-movement sleep. Although slow spike-waves
are often associated with an ictal pattern (ie, during a
seizure), they can be interictal in many cases and, as such,
might not be associated with any clinical correlate, such
as staring or confusion. The abundance and the waxing
and waning characteristics of slow spike-waves commonly
blur any distinction between ictal and interictal patterns.
Slow spike-waves can therefore be distinguished from
3 Hz spike-wave discharges, which are usually associated
with a clinical change if their duration is longer than 3 s.
In addition, photic stimulation in patients with LGS
typically fails to “activate” slow spike-waves, which
distinguishes LGS from some myoclonic epilepsies.
Bursts of diffuse or bilateral fast rhythm patterns (10 Hz
or more) or “polyspikes”, also called generalised
paroxysmal fast activity, are recorded during slow sleep
(figure 1). These bursts last for a few seconds but tend to
recur at brief intervals18,19 and are almost identical, but
shorter, to the bursts commonly seen in clinical tonic
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seizures that have a “recruiting” rhythm—an initial
lowering of amplitude followed by a gradual increase in
amplitude (recruitment). Although these patterns might
seem to have no clinical correlate, polygraphic recordings
can identify a brief apnoea or a mild electromyographic
axial contraction; therefore, a recording of non-rapid-eye-
movement sleep might be needed to indicate their
presence. Generalised paroxysmal fast activity occurs
more commonly in patients with LGS (79%) than in
patients who have slow spike-waves as a result of focal
epilepsies with secondary bilateral synchrony (15%), and
this can be used to discriminate between the two.20
Diagnostic issues and differential diagnosis
The diagnosis of LGS depends on the combination of the
electroclinical criteria as defined above. The predominance
of tonic seizures and patterns of fast rhythms are probably
the most indicative features of the syndrome. However,
these features are not necessarily present at onset, many
other types of seizures can appear first, tonic seizures are
not always easy to detect, and an EEG recording during
sleep might be mandatory. The clinical presentation of
LGS remains heterogeneous and the multiple causes that
can be associated with the syndrome can also affect
prognosis or sometimes therapeutic strategies.
Attention to the criteria defined above for diagnosis of
LGS should remove from consideration many similar
disorders in most patients. However, as with any epilepsy
disorder, the boundaries between syndromes might be
blurred. For example, infantile spasms and hypsarrhythmia
can gradually progress to LGS with slow spike-waves,
which accounts for about 20% of all cases of LGS.21
Distinctions between a long spasm (>1 s) and a short
tonic seizure can be arbitrary,1 but the tendency of spasms
to cluster might help to distinguish between the two types
of seizures. Among patients who present between the ages
of 2 and 5 years, seizures at onset might be prominently
myoclonic or myoclonic-astatic, there might be episodes of
non-convulsive status epilepticus, and the EEG recording
might variably feature fast spike-wave complexes and slow
spike-wave complexes,22 which suggests the clinical picture
characterised as Doose’s syndrome. In a second phase of
evolution, some of these patients will develop tonic seizures
and a picture that fulfills the main criteria for LGS.9
Differential diagnosis at onset is difficult in the absence of
biological markers, particularly for cryptogenic cases.23
However, other epilepsy syndromes with an early onset in
childhood (eg, early-onset childhood absence epilepsy or
Dravet’s syndrome) differ from LGS in initial clinical
presentation, course, prognosis, and therapy, and should
not be confused with LGS. Some examples of EEG
abnormalities that might be clinically confused with LGS
are shown in figure 2.
A more difficult problem for diagnosis is atypical benign
partial epilepsy,17,24 which is also known as pseudo-Lennox
syndrome.25 Children with atypical benign partial epilepsy
present with multiple falls and diffuse EEG abnormalities
www.thelancet.com/neurology Vol 8 January 2009
Review
on sleep recordings. The course of the disorder in these
patients is characterised by active periods with multiple
falls separated by almost seizure-free intervals that can
last several months. Recording of episodes of “continuous
spike-waves of slow sleep” usually enable differential
diagnosis of LGS at an early stage of the disorder. Moreover,
tonic seizures and generalised paroxysmal fast activity do
not occur in these patients. Patients with atypical benign
partial epilepsy are important to distinguish because this
type of epilepsy typically remits by adolescence.
Focal and secondarily generalised seizures that
originate in the frontal lobe can also produce bilateral
tonic features, although these are usually asymmetrical
early in the seizure (Blume WT, personal communication).
Furthermore, these patients will sometimes have EEG
recordings that show generalised spike-wave discharges
as a manifestation of rapid spread across the corpus
callosum (secondary bisynchrony). The possibility of
secondarily generalised seizures should be taken into
account if the neurological examination, interictal or ictal
EEG recording, or neuroimaging scan show relevant
lateralised abnormalities.
In summary, the diagnosis of LGS depends on a
conjunction of clinical and EEG abnormalities. There is a
risk for underdiagnosis because some types of seizures
might occur many months before the initial appearance
of slow spike-waves1,10 and EEG recordings of sleep are
not always available. However, because EEG recordings
during sleep are required for the diagnosis of LGS, these
should be made available to the clinician during
diagnosis. Conversely, there is also a risk for overdiagnosis
of LGS: a diagnosis for this syndrome should not depend
only on the presence of slow spike-wave discharges on
EEG recordings; furthermore, patients with only tonic
seizures or drop attacks do not necessarily meet the
criteria of LGS.
Management issues
Results of trials
Randomised controlled trials have been done in patients
with LGS to study the effects of lamotrigine, topiramate,
felbamate, rufinamide, an analogue of thyrotropin-
releasing hormone, and cinromide (table 1).26–30 A
Cochrane review of randomised controlled trials of
treatments of LGS concluded that lamotrigine,
topiramate, and felbamate might be helpful as add-on
therapies for patients with this syndrome.31 A decrease in
the frequency of all seizures was found for patients taking
lamotrigine compared with placebo (–32% vs –9%;
p=0·02)28 and felbamate compared with placebo (–19% vs
+4%; p=0·002),27 whereas the decrease in total seizure
frequency for topiramate did not reach statistical
significance (–21% vs –9%).29 The frequency of drop
attacks decreased significantly after lamotrigine28 or
topiramate.29 Felbamate significantly lowered the
frequency of atonic seizures;27 the term “atonic seizures”
was probably used to indicate drop attacks in that study.
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 Review

The frequency of tonic-clonic seizures decreased on

A Awake Asleep treatment with lamotrigine and felbamate but was not
reported as a unique measurement for topiramate. The
frequency of atypical absence seizures was not affected
by lamotrigine and was not reported for topiramate and
felbamate; however, these studies were not designed to
assess the effect on this type of seizure because these are
usually uncountable owing to their high frequency.
L Delt Neither cinromide nor the analogue of thyrotropin-
releasing hormone showed any benefit in the treatment
of LGS.26,32
Rufinamide, a drug that was granted orphan drug
status for the adjunctive treatment of LGS in the USA in
2004 and marketing authorisation in Europe in 2007,
significantly reduced the frequency of total seizures
compared with placebo (–32·7% vs –11·7%; p=0·0015)
R Delt
and tonic-atonic seizures compared with placebo (–42·5%
Fz–Cz
R Ext
vs +1·4%; p<0·0001) in a randomised controlled trial.30
100 μV Furthermore, the benefit of rufinamide was maintained
1s
during the 3-year follow-up.33
B Sleep stage II
Uncontrolled studies with valproic acid found a greater
than 50% improvement in seizure control in 55% of
patients with drop attacks (although whether patients
with LGS were included in the study is not clear) and in
25–30% of patients with atypical absences and myoclonic
seizures.34–37 Lower responder rates were reported for
tonic and tonic-clonic seizures.34–37 In uncontrolled, small
L Delt
trials that studied the effect of benzodiazepines in
patients with LGS, improved seizure control was reported
in 46–70% of patients.38–41 Clobazam is being investigated
Figure 2: Examples of EEG abnormalities that might be clinically confused
with LGS
(A) Polygraphic EEG recording of a 4-year-old boy with atypical benign rolandic
epilepsy. On the left, the child is awake with his arms raised. Interference from
muscular activity, as recorded with surface electrodes, is interrupted by isolated or
repetitive electrical silent periods (negative myoclonus) during which the child
staggers or falls. The EEG recording shows diffuse discharges of sharp and slow
R Delt wave complexes, which are commonly time locked to the electromyographic
silent periods. On the right, the child is asleep. Continuous spike and wave
Fz–Cz
discharges are seen that include the entire hemisphere (right) and the
PNO centrotemporal leads (left). Atypical benign rolandic epilepsy has also been
defined by some authors as pseudo-LGS because of its association with atonic
100 μV attacks and with an EEG recording with abundant spike discharges or sharp-and-
1s
slow wave discharges. (B) EEG recordings of a boy with pachygyria while asleep. At
C Unresponsiveness 3 min after diazepam administration 4 years of age (left) there are no EEG abnormalities during sleep. After 6 months
(right), the boy has had two generalised clonic seizures and the EEG recording
shows continuous generalised spike discharges and slow wave discharges during
sleep. This recording is suggestive of an initial form of epilepsy with continuous
spike-and-wave activity during sleep; however, the EEG pattern when asleep is
similar, in this case, to what can be seen in LGS. (C) A 10-year-old boy with a
malformation of the left temporal lobe. The patient has subcontinuous episodes
L Delt of prolonged unresponsiveness that are clinically similar to the non-convulsive
status of LGS. The EEG recording (left) shows a period of unresponsiveness, during
which bilateral and synchronous, nearly continuous, irregular, high-amplitude,
rhythmic spike and slow wave are seen. Note that the more diffuse discharges are
preceded by a series of spikes on the left. The clinical and electrographic episode is
interrupted by the intravenous administration of diazepam (right). However,
sporadic bilateral synchronous frontocentral spike and wave discharges continue
after diazepam is given. This disorder indicates episodes of unresponsiveness that
R Delt are associated with secondary bilateral synchrony and not with typical generalised
Fz–Cz atypical absence status. EEG=electroencephalogram. Fz–Cz=fronto–central midline
100 μV
1s EEG recording. L Delt=left deltoid. LGS=Lennox-Gastaut syndrome.
PNO=recording of respiration. R Delt=right deltoid. R Ext=right wrist extensor.

86 www.thelancet.com/neurology Vol 8 January 2009

 Review

Cinromide26 Felbamate27 Lamotrigine28 Topiramate29 Rufinamide30

Age range (years) 3–18 4–36 3–25 2–29 4–36
Number of patients 56 73 169 98 138
EEG criteria SSWs in prior 3 months SSWs Recent EEG with SSWs Prior EEG with SSWs SSWs in prior 6 months
Seizure type
Drop attacks Yes Yes Yes Yes Yes
Atypical absence Yes Yes +/– +/– +/–
Generalised tonic-clonic +/– +/– Yes +/– +/–
Myoclonic Yes +/– +/– +/– +/–
Partial +/– +/– +/– +/– +/–
Number of seizures per month† >80 90 15 60 >90
Methods for counting seizures Diary Diary and video EEG Diary Diary Diary
Initial video EEG Not done Done Not done Done Done
Number of concomitant 1–3 1–2 1–3 1–2 1–3
antiepileptic drugs
Trial period (weeks)
Baseline 6 4 4 4 4
Titration 6 2 6 3 2
Maintenance 12 8 10 8 10

+/–=seizures counted if present. EEG=electroencephalogram. SSW=slow spike-waves. Yes=required or target seizure type.*All studies had an add-on design. †Approximate
evaluation of the number of seizures at baseline.

Table 1: Methodological features of major randomised, placebo-controlled trials of antiepileptic drugs in patients with Lennox-Gastaut syndrome*

in a phase II trial in the USA as an adjunctive therapy for
drop attacks in patients with LGS. This drug is used, on
the basis of clinical practice, in several European
countries and Canada.9 Other antiepileptic drugs for
which there are published reports of open trials in
patients with LGS include levetiracetam, ethosuximide,
vigabatrin, and zonisamide.42–47
Favourable results in patients with LGS have been
reported with adrenocorticotropic hormone or
steroids.15,48–50 Everyday clinical practice suggests that
steroids might occasionally have a major effect, particularly
for the control of atypical absences, drop attacks, and
prolonged episodes of non-convulsive status epilepticus.
However, no controlled study of steroids is available as yet
and relapse seems common. Recent experience seems to
be moving away from long-term therapy with these drugs
that are used more often in some patients during
particularly difficult periods of exacerbation.9
The use of intravenous immunoglobulins in high doses
has shown some encouraging results;51 however,
controlled trials of immunoglobulins have not confirmed
these results.52,53
The ability of some AEDs to potentially exacerbate the
frequency of seizures is a serious and common clinical
problem that should not be overlooked. For example,
benzodiazepines can occasionally cause tonic seizures,
particularly when given intravenously to control other
seizure types in patients with LGS.54 Although the
mechanism of drug-induced aggravation of seizures is
poorly understood, this might relate to the incorrect
diagnosis of seizure type or epileptic syndrome, the
incorrect choice of drug (eg, the use of an antiepileptic
drug contraindicated for use in specific types of epilepsy),
or drug doses or drugs combinations that are excessive.54
Treatment guidelines
Treatment options for patients with LGS are limited
because of the resistance of seizures to pharmacological
treatment. In addition, as there is no animal model for
LGS, progress in our understanding and treatment of this
disorder is impeded because novel targets for intervention
cannot be rigorously studied. The choice of the most
appropriate antiepileptic drugs is complex and there is
little guidance available for the practising physician. Owing
to the many seizure types, many drugs are used in
combinations that are mostly guided by anecdotal evidence
or personal experience. Opinions towards treatment are
further complicated because an antiepileptic drug might
be of some benefit for the control of one type of seizure
while aggravating another type. Concomitantly, polytherapy
increases the potential for adverse events.
Only a few controlled studies of treatments are available
and these have usually been designed to assess the efficacy
of a drug on one or two types of seizures. As yet, no study
is available that has investigated the early overall effect of a
drug on the global progression of the syndrome. Guidelines
from the American Academy of Neurology have assessed
the data on the efficacy and safety of seven new antiepileptic
drugs for the treatment of refractory epilepsy, including
LGS.55 Older drugs established in clinical practice are not
included in these guidelines. An earlier assessment of
felbamate found that this drug was appropriate for therapy

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 Review

treatment of drug-resistant partial and generalised seizures

Panel 2: Summary of management considerations of LGS rather than LGS specifically.57,58 A summary of the
General considerations considerations for the management of LGS is provided in
• No results from class I or II studies are available for the treatment of LGS at onset or panel 2.9,15,27–30,56,57,59 The limited guidance available for the
early in the course of the disorder. The suggestions that follow derive from clinical practising physician means that clinicians frequently rely
experience and surveys from experts on clinical judgment. For example, in a survey sent to
• Controlled studies with felbamate, lamotrigine, topiramate, and rufinamide included 57 physicians in Europe who specialised in paediatric
patients with an already well established epileptic encephalopathy epilepsy, the participants were asked to recommend overall
treatment approaches for specific syndromes, including
Management at onset the order in which treatments should be used.59 Initial
• Follow-up with an epilepsy specialist is essential from onset, both for diagnostic and therapy with valproate was recommended as the first-line
management reasons treatment of choice for LGS. If initial monotherapy was
• An EEG recording during sleep is mandatory to confirm diagnosis. If normal at the early not successful, 57% of the physicians who responded
stages, an EEG recording should be repeated when justified by the clinical progression recommended a combination of two antiepileptic drugs,
• Clinical experience and data from class III or IV studies suggest that antiepileptic drugs whereas 38% of respondents advised a different
with a broad range, such as sodium valproate, benzodiazepines, and lamotrigine, monotherapy at the second step of treatment if first-line
should be used at the early stages of the disorder, when drop attacks are the treatment failed. Monotherapy with lamotrigine was the
predominant, if not the only, type of seizures. Broad-range antiepileptic drugs might next treatment of choice if initial monotherapy was un-
also be effective against atypical absence seizures successful, and topiramate was another first-line option.59
Management during the state period* In a similar survey in the USA, respondents recommended
• Long-term treatment can be deceptive. Experience has shown the danger of excessive valproate as the initial monotherapy of choice, followed by
therapy because the use of a combination of several antiepileptic drugs might topiramate as the next option; lamotrigine was advised as
facilitate episodes of non-convulsive status epilepticus or tonic status and increase the another first-line option.60 Of the responses, 81% endorsed
risk of adverse events. A good knowledge of antiepileptic drug interactions is required a trial of a different monotherapy for the second step in the
when treating children or adolescents with LGS treatment pathway.60 Opinion obtained from specialised
• Benzodiazepines can be effective against all types of seizures, including tonic seizures physicians in surveys such as these can provide helpful
(preferably at a low dose). Clobazam, when widely available (so far, approved in most guidance in situations where there are limited medical
European countries and Canada), is expected to be preferred to nitrazepam and publications available.
clonazepam because of the lower sedative effect. The efficacy of benzodiazepines is Owing to the need for combination therapy, patients and
commonly variable, which means these need to be used alternately with other drugs caregivers should be informed of the increased risk of
• Corticosteroids and adrenocorticotropic hormone could be tried early in the course of adverse events, independently of the antiepileptic drugs
the syndrome or used occasionally during periods of electroclinical aggravation chosen. The limitations of treatment, the waxing and
• Carbamazepine can be used to control tonic seizures but the use of this drug requires waning in the progression of seizure frequency, and the
vigilance to detect any aggravation of certain types of seizures (eg, atypical absences, rare but potential exacerbation of symptoms by some
myoclonic seizures, and episodes of non-convulsive status) antiepileptic drugs54 also need to be carefully explained to
• Felbamate, lamotrigine, rufinamide, and topiramate are indicated for the control of patients. Furthermore, various behavioural and psychiatric
drop attacks (see text) comorbidities are commonly seen in children with LGS
• Anecdotal reports and data from open studies have indicated some efficacy with (including attention-deficit hyperactivity disorder, anxiety,
zonisamide and shown no aggravation of seizures with the use of levetiracetam. aggressive behaviour, psychosis, and depression) and these
• Management of LGS requires a multidisciplinary medical and psychosocial team. comorbidities should also be considered when choosing
Comorbidities should also be treated by specialists an antiepileptic drug.61 Careful attention should be paid to
potential direct and indirect effects of antiepileptic drugs
EEG=electroencephalogram. LGS=Lennox-Gastaut syndrome. Data from references 9,15,27–30,56,57,59. *The clinical picture
that might result in aggravation of such comorbidities,
remains relatively stable in comparison to the onset period.
through drug–drug interactions or adverse behavioural
and psychiatric side-effects.62 However, no controlled trials
or guidelines are available for the treatment of comorbidities
only after other drugs had failed because of the risk of life- in children with LGS. Therefore, children with LGS who
threatening toxicity.56 On the basis of the limited data have comorbid psychiatric and behavioural disorders
available, the guidelines of the American Academy of would benefit from parallel neuropsychological and
Neurology concluded that lamotrigine and topiramate— psychiatric assessment by a child psychiatrist to obtain
the only drugs in addition to felbamate for which class I optimum diagnosis and treatment.63,64
evidence of efficacy was available from randomised
controlled trials—can be used to treat the drop attacks Pharmacokinetic aspects and concentration-response
associated with LGS; furthermore, felbamate might have a relationships
role in the treatment of LGS.55,56 Recommendations from Because antiepileptic drugs have a narrow therapeutic
other guidelines also rely on data from published index and a variable dose-response relationship, doses
randomised controlled trials and discuss options for the should be tailored for each patient for therapeutic

88 www.thelancet.com/neurology Vol 8 January 2009


success.65 Patients with LGS have a larger variability in
their pharmacokinetic response than other populations
with other forms of epilepsy, partly because of age and
partly because of their frequent polytherapy.66 Despite
evidence that the pharmacokinetics of most antiepileptic
drugs are different in young children compared with
adults,67 there are limited data on how the pharmaco-
kinetics of antiepileptic drugs vary according to age,
bodyweight, and body surface area. Drug interaction
data from adults might also not be readily extrapolated
to children because of age-related changes in drug
metabolism and patterns of co-medication exposure.
Failure to compensate for major pharmacokinetic
changes could result in underdosing or overdosing;
therefore, more pharmacokinetic studies of antiepileptic
drugs in paediatric populations are needed.
More data are also needed to discern the association
between serum drug concentration and clinical response.68
Optimum responses to antiepileptic drugs are obtained at
different serum drug concentrations in different patients
and are dependent on the type of seizure and epilepsy
syndrome;69 therefore, studies in patients with LGS are
needed. Responsiveness to the concentration of a particular
antiepileptic drug, including adverse effects, can also be
affected by age and co-medication.65,70 Characterisation of
the concentrations associated with optimum responses in
individuals (and an analysis of the covariates that are
implicated) could improve the clinical management of
these patients.70–72
Non-pharmacological management
Complete or partial callosotomy is the primary palliative
surgical treatment for children with LGS who have
frequent seizures that cause drop attacks. Complete
resection will probably lead to fewer drop attacks;
however, complete resection is not always technically
possible. The effect of total or partial corpus callosotomy
on cognitive functioning, social adjustment, and motor
behaviour needs to be studied further, particularly if this
procedure is to be used in children with only moderate
cognitive impairment.73–75 Callosotomy has been
associated with improved control of atonic or tonic
seizures, although lower success rates have been reported
for generalised tonic-clonic seizures.76–78
Stimulation of the vagus nerve might also help in the
treatment of drop attacks. This treatment has a lower
morbidity risk than callosotomy does and has also been
used as an adjunct to the callosotomy procedure.79,80
Several open, prospective trials have assessed the response
of patients with LGS to stimulation of the vagus nerve.
After 6 months of vagus nerve stimulation, a median
reduction in total seizure frequency of 46–58% was
reported,81,82 whereas atonic seizures decreased by 88%.82
The long-term follow-up of vagus nerve stimulation in
children with LGS has indicated no adverse effects in
behaviour, and positive changes in behaviour were noted
in some patients.83
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Review
A ketogenic diet can improve seizure control for some
patients with LGS. The atonic and myoclonic seizures
associated with LGS decreased rapidly by more than 50%
in children on a ketogenic diet.84
Preliminary results with electrical stimulation of the
centromedian thalamic nucleus have also been reported
for generalised seizures.85 The overall frequency of
seizures was reduced by 80% in 13 patients with LGS and
a subsequent improvement in independence of patients
and a decreased dependence on caregivers was seen.85
Although some of the results of these studies are
promising, these data are difficult to interpret because of
the uncontrolled design of the trials and, in many studies,
concurrent changes in associated antiepileptic drug
therapies.
Treatment considerations: global assessment and
outcome
Seizures are not the only manifestation of many epilepsy
syndromes, and the associated comorbidities are of
concern, particularly the effects on behaviour and
cognition. This is specifically the case for LGS, in which
patients are not only impaired in their everyday lives by
drop attacks that are often frequent, difficult to treat, and
can cause injury, but also by impairments in cognition
and behaviour. These cognitive and behavioural
impairments are often difficult to quantify in the short
and long term but need to be considered when comparing
one treatment with another.
Contrary to the conventional management of epilepsy,
the aim of treatment of LGS is often to suppress or
reduce the frequency of the more disabling types of
seizures rather than complete freedom from seizures
(although this would be the ultimate aim). The more
complex aspects of LGS, such as the occurrence of non-
convulsive status epilepticus or the effects of the epilepsy
syndrome on cognition and behaviour compared with
the effects of the medication are difficult to quantify over
a short response time to treatment. Many of these
problems are not assessed in short-term clinical trials,
which typically measure efficacy over only 10–16 weeks.
The age range is also broad and, owing to the progression
of the syndrome and the different expectations at
different ages, the aims for benefit in treatment might
differ in accordance with the stage of the disease. For
example, newly diagnosed children might have had a
catastrophic onset of epilepsy with developmental arrest;
the aims of therapy in such a case would be to reverse, at
least in part, the cognitive impairment and behavioural
abnormalities of the child. However, in an older child,
who might have had several years of treatment, the
expectations might be reduced frequency of seizures
rather than specific changes in cognition. Improved
control of seizures can result in greater alertness, which
might translate into altered behaviour of the patient;
this change could potentially be misunderstood as a
behavioural side-effect of the treatment.
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 Review
Because seizures in LGS tend to be resistant to treatment,
seizure reduction should not be pursued at all costs. It is
not uncommon for the patient’s quality of life to be
impaired more by the side-effects of treatment than by the
seizures themselves. Physicians should always be vigilant
for adverse drug effects, particularly on coordination,
cognition, and behaviour, and should not increase doses
or the number of drugs when considerable adverse effects
are already present. In some cases, excessive drug loads
can paradoxically increase the frequency of seizures, which
can result in more aggressive treatment and thus further
increase the severity of seizures.54
Agreement of written treatment goals with parents,
caregivers, and the patient, if possible, could be made
before selecting a treatment plan. A global outcome
assessment can then be measured in accordance with the
treatment plan for each patient. Assessments of the quality
of life are more important in the long term than
measurements of seizure outcome. Therefore, the
management of patients with LGS and any consideration
of the effect of a new treatment has to account for all
aspects of quality of life, and any study of efficacy has to
ideally measure change during an appropriate length of
time. Such measurement is difficult in placebo-controlled,
add-on studies because of ethical reasons; these studies
usually have a maximum duration of placebo treatment of
4 months as cognitive and behavioural regression might
proceed during longer placebo periods. However, active
control trials, which might have a longer duration, could
be done in the future. Ideally, the outcome assessment
should be undertaken over no less than 6 months.
Another way to enable assessments over the long term
would be to use standardised measures of cognitive
performance and behaviour. Specific subtests of
standardised scales could provide a means to monitor
specific aspects of cognition. A further possibility would
be to use the International Classification of Function,
Health, and Disability (ICF)86 to plan intervention and
Dimensions of ICF 4-year-old patient 12-year-old patient
Body functions and • Do the causes of LGS alone predict mental retardation and • Can there be a further effect on cognition
structures other neurological disorders or can seizure control prevent with improvement in seizures?
cognitive or behavioural decline? • Is freedom from seizures possible?
• Is freedom from seizures possible? • What is the effect of medication on
• What is the effect of medication? behaviour or cognition?
• Does control of seizures contribute to paradoxical change
in behaviour?
Activity and • Pre-school education • Integration and schooling
participation • Injuries • Relationships with peers
• Interaction with peers • School trips
• Out-of-school activities
Environmental • Burden on the family with brothers and sisters • Attitude of school
factors • Parental employment • Burden on the family
• Residential schooling?
• Risks of sudden unexpected death?
ICF=International Classification of Function, Health, and Disability. LGS=Lennox-Gastaut syndrome.
Table 2: Examples of different aspects of global assessment according to the ICF model for a 4-year-old patient, a 12-year-old patient, and a 35-year-old patient with LGS
90
research studies in LGS. Functioning of the patient in
the ICF model is described as the dynamic interaction
among three dimensions: body functions or structures;
activity and participation; and environmental factors.
This is now widely internationally used in rehabilitation
outcome research, and the use of this model in the
assessment of patients with LGS is a challenge. An
example of global assessment using the ICF model is
shown in table 2. However, the ICF model was developed
for the assessment of stable disorders such as
psychomotor disabilities; therefore, the application of
this model for the assessment of paroxysmal disorders
such as epilepsy will need thorough investigation.
Methodological issues for future trials
In the past decade, a formalised clinical trial strategy has
been devised for the study of the therapeutic effects on
LGS on the basis of the substantial treatment effects of
felbamate, lamotrigine, topiramate, and rufinamide
(table 1).26–30
The difficulty in characterising LGS makes the design
of clinical trials of this disorder difficult. Most types of
seizures can be frequent and the ability to determine the
onset, duration, and eventual repetition of individual
events correctly, compared with prolonged seizures, is
sometimes nearly impossible. Often, only the most
severe seizures, such as those that cause drop attacks, are
the ones that can be recorded easily. Postictal lethargy
and confusion might also be impossible to distinguish
clinically from atypical absence seizures, even with
constant observation; constant monitoring might only
just be achieved with video EEG recording. Nocturnal
tonic seizures, although sometimes frequent, might not
be as easy to identify as ictal events, even with EEG
monitoring over 24 h. The problems encountered in the
trial of cinromide is one example of the difficulty of doing
studies in which all daily seizures are counted:26 in this
trial, no difference in seizure frequency was seen between
35-year-old patient
• Can better control of seizures result in improved mental
or behavioural functions?
• Is freedom from seizures still possible?
• Do antiepileptic drugs that failed in the past now have a
different effect?
• Does control of seizures contribute to paradoxical change
in behaviour?
• Self-independence
• Mobility
• Working
• Social interaction
• Living outside the family
• Partnership
• Risks of sudden unexpected death?
www.thelancet.com/neurology Vol 8 January 2009

the treatment and placebo groups, possibly because
parents could not distinguish seizures from other
behavioural activities.
Other problems in the design of clinical studies in LGS
relate to the criteria for enrolment, which should be
consistent with the definition of LGS. Entry criteria for
specific EEG characteristics must be clearly defined and
should be standardised among study centres. The
provision of definitions for types of seizures and
specifications for the number and type of concurrent
therapies and rescue therapies allowed during the course
of the trial are also important. Although drop attacks
have historically formed the basis for inclusion in trials,
because they are easily countable, other types of seizures
should also be considered.
The duration of epilepsy before enrolment in a clinical
trial can also be crucial. At onset, LGS has some of the
characteristics of a progressive disorder (ie, the
appearance of new types of seizures, deterioration of the
interictal EEG recording, and an effect on cognitive
development). Consequently, LGS is commonly suspected
but not actually confirmed. Additionally, the effect of
drug treatment might be different in patients who
progress to the later stages of LGS than in patients who
have had a more stable form of the disorder for longer.
The identification of antiepileptic drugs that can stop the
progression of the syndrome towards an epileptic
encephalopathy would be welcomed. Current trials can
assess the ability of a new drug to stabilise the disorder
only when it has already reached a devastating plateau. The
acceptance of broader enrolment criteria and the long-term
identification of “pure” or “incomplete” LGS would provide
us with results that are more clinically meaningful.
Novel endpoints and measurements for improvement
instead of a reduction in seizures (eg, effects on cognition,
behaviour, and quality of life) should also be investigated.
Quality-of-life measures tailored to LGS and consideration
of different aspects of an individual’s epilepsy (eg, severity
of seizures, concurrent seizures, duration of seizures,
and number of days without drop attacks) might be
useful indications of the actual everyday benefits of a
treatment. Specific strategies should also be sensitive
enough to detect worsening—or improvement—of
different types of seizures.
Conclusions
Given the need to develop further therapies for patients
with LGS, the orphan drug designation procedure in the
USA is a practical approach that encourages the devel-
opment of drugs for the treatment of severe and rare
disorders, such as LGS. Although orphan drug status is not
a marketing authorisation, this approach encourages the
development of drugs that are necessary for the treatment
of rare diseases but that would be prohibitively expensive or
unprofitable to develop under normal circumstances.
Diagnosis of LGS is not difficult if strict criteria are used:
several types of seizures (including tonic seizures),
www.thelancet.com/neurology Vol 8 January 2009
Review
Search strategy and selection criteria
References for this Review were identified through searches of
PubMed by use of the search terms “aetiology”, “antiepileptic
drugs”, and “Lennox-Gastaut syndrome” in combination with
“diagnosis”, “EEG”, “slow spike waves”, and “randomised
controlled trial”, between January, 1950, and August, 2008.
All randomised controlled trials of LGS were included in this
Review. Only papers published in English, French, and German
were reviewed. The final reference list was generated on the
basis of relevance to the topics covered in this Review.
interictal slow spike-waves, spikes and bursts of 10–20 Hz
spikes during sleep, and impairments in cognition. The
core types of seizures (ie, tonic and atonic, atypical
absences, and episodes of non-convulsive status
epilepticus) can be variably associated with attacks that are
thought to be less characteristic, such as tonic-clonic,
partial, or unilateral seizures. However, early diagnosis can
be difficult, and an early referral to an epilepsy specialist is
important because not all indicators of LGS are present at
onset and none of the typical features are pathognomonic.
Despite the availability of several new antiepileptic
drugs, which have been validated through well-designed,
randomised, controlled trials for the treatment of drop
attacks in LGS, this disorder is still one of the most
challenging epileptic encephalopathies to the treating
physician, the companies that design clinical trials and
develop therapies, the regulatory authorities, and, of
course, to the patients and their families.
A more holistic approach to the investigation of the
effects of newer medications might help to identify
treatments that, when used in the early stages of the
disorder, might have long-term beneficial effects on
seizures and the associated comorbidities.
Contributors
AA participated in the preparation of the first draft of the Review,
discussed contributions from all co-authors, and approved the final
version. JF participated in the writing and editing of the Review. WTB
participated in the section on the concerns for diagnosis and differential
diagnosis. JHC participated in the discussion, writing, and final editing
of the Review and prepared the section on treatment considerations with
regard to outcome. J-PE participated in the section on non-
pharmacological treatments. MF participated in the meeting that formed
the basis of the Review, particularly on the review of recent studies to
assess the effects of standard and new antiepileptic drugs in LGS. PG
provided publications that were used in the drafting of this Review. RG
participated in the planning of the Review, as well as the writing of some
parts and critical review at an advanced draft stage. GK participated in
the writing and reviewing of the Review. JMP participated in the writing
and editing of the Review. EP and JWW participated in the writing of the
Review.
Conflicts of interest
AA has received speaker payments, consultancy fees, and/or research
grants from Cyberonics, Eisai, GlaxoSmithKline, Johnson & Johnson,
Novartis, Pfizer, Sanofi-Aventis, Schwartz Pharma, UCB Pharma, and
Valeant. JF has consulted on behalf of Eisai, but received no personal
income. Consulting fees have been accepted by either the Epilepsy Study
Consortium or the Department of Neurology at the University of
Pennsylvania. The total amount was US$<10 000. JF has spoken on
91
 Review
behalf of Eisai in satellite symposia at international epilepsy meetings in
2007 and 2008: the honoraria from these went to the Department of
Neurology at the University of Pennsylvania, and the New York Epilepsy
and Neurology PLLC, respectively. In both cases, travel to the speaking
events was reimbursed. JHC has received honoraria and educational
grants from Janssen Cilag, UCB Pharma, Eisai, and SHS International.
J-PE has received speaker payments, consultancy fees, and/or research
grants from Eisai, Janssen Cilag, Novartis, Sanofi-Aventis, UCB Pharma,
and Desitin. MF has received consultation, advisory board, and speaking
honoraria from Eisai, Gerot Pharmaceuticals, GlaxoSmithKline, Jannsen
Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB Pharma, and Cyberonics.
JMP has received speaker payments, consultancy fees, and/or research
grants from the National Institutes of Health, the National Institute of
Neurological Disorders and Stroke, Abbott Laboratories, AstraZeneca,
Aventis, Cephalon, Eisai, GlaxoSmithKline, Jazz Pharmaceuticals,
King Pharmaceuticals, KV Pharmaceuticals, Marinus Pharmaceuticals,
MedPointe, Neurpace, Novartis, Ortho-McNeil, Johnson & Johnson,
Ovation, Pfizer, Questcor, Schwarz Pharma, UCB Pharma, and Valeant.
EP has received speaker payments, consultancy fees, and/or research
grants from Bial, Cyberonics, Eisai, GlaxoSmithKline, Johnson &
Johnson, Novartis, Ovation, Pfizer, Sanofi-Aventis, Schwartz Pharma,
SK Holdings, UCB Pharma, and Valeant. JWW has received grants and/
or speaker payments and/or consultancy fees from the National
Institutes of Health, Shainberg Foundation, Abbott, UCB Pharma,
GlaxoSmithKline, Ovation, Questcor, Marinus, Ortho-McNeil,
King Pharmaceuticals, Cyberonics, Novartis, Pfizer, Eisai, Shire
Pharmaceuticals, Valeant, Cydex, and Neurelis. WTB, PG, RG, and GK
have no conflicts of interest to declare. None of the authors received
financial support or honoraria for the preparation of this paper.
Acknowledgments
All authors of this Review participated in an expert consensus meeting
on LGS funded by Eisai Europe. The discussions raised at this meeting
formed the basis of this Review. The first draft of the paper was prepared
by AA and then given to all authors for specifc contributions on the basis
of their specialist field. AA also used a summary of the meeting that was
produced by a medical writer (ACUMED) at the request of Eisai. The
sponsor had no part in the content of this Review. The authors thank
K de Saram at Complete Medical Communications who provided
editorial assistance.
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