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Review

Lennox-Gastaut syndrome: a consensus approach on


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

Lancet Neurol 2009; 8: 82–93 Lennox-Gastaut syndrome is one of the most severe epileptic encephalopathies of childhood onset. The cause of this
Institute for Children and syndrome can be symptomatic (ie, secondary to an underlying brain disorder) or cryptogenic (ie, has no known cause).
Adolescents with Epilepsy– Although Lennox-Gastaut syndrome is commonly characterised by a triad of signs, which include multiple seizure
IDEE, University Hospitals of
types, slow spike-wave complexes on electroencephalographic (EEG) recordings, and impairment of cognitive function,
Lyon and INSERM U821, Lyon,
France (A Arzimanoglou MD); there is debate with regard to the precise limits, cause, and diagnosis of the syndrome. Tonic seizures, which are
NYU Comprehensive Epilepsy thought to be a characteristic sign of Lennox-Gastaut syndrome, are not present at onset and the EEG features are not
Center, New York, USA pathognomonic of the disorder. There are few effective treatment options for the multiple seizures and comorbidities,
(J French MD); Department of
and the long-term outlook is poor for most patients. Probably as a result of the complexity of the disorder, only a few
Clinical Neurological Sciences,
Epilepsy and Clinical randomised trials have studied Lennox-Gastaut syndrome, and thus many of the drugs that are more commonly used
Neurophysiology, London have little or no supporting evidence base from controlled trials. In this Review, we discuss the main issues with
Health Sciences Centre– regard to the diagnosis and treatment options available. We also suggest key considerations for future trials and
University Campus, London,
Ontario, Canada
highlight the importance of a comprehensive approach to the assessment and management of this syndrome.
(W T Blume MD); University
College London–Institute of Introduction Characterisation of LGS
Child Health, London, UK Lennox-Gastaut syndrome (LGS) is a severe form of History
(J H Cross MD); Epilepsieklinik
für Kinder und Jugendliche
epilepsy with childhood onset. LGS can occur as a The electroclinical syndrome was identified by the
Epilepsiezentrum Kork, Kehl, secondary result of an insult to the brain either during the Marseille School in France in 1966,1 after the medical thesis
Germany (J-P Ernst MD); prenatal, perinatal, or neonatal periods, or can occur in an of Dravet2 and the publications of Gastaut and co-workers3
Department of Pediatrics, otherwise previously healthy child. Seizures associated and Sorel.4 Gastaut and co-workers1 suggested the term
Epilepsy Service and EEG
Laboratory, Medical University
with LGS might occur de novo or might follow severe “Lennox syndrome” to describe an epileptic encephalopathy
of Vienna, Vienna, Austria infantile seizure disorders, such as infantile spasms. LGS that had a childhood onset, diffuse slow spike-wave
(M Feucht MD); Centre Saint is associated with many types of seizures (including tonic, complexes, and several types of seizures (including tonic
Paul, Hôpital Henri Gastaut, atonic, and atypical absences), moderate to severe seizures), as had been first reported by Lennox and Davis.5
Marseille, France
(P Genton MD); Pediatric
cognitive dysfunction, and the persistence of seizures into The term “Lennox-Gastaut syndrome” was introduced
Neurology Unit, Children’s adulthood. In addition to concerns about social integration later6 and gained wide acceptance, even though the criteria
Hospital A Meyer, University of and care, LGS is one of the most complex epileptic for the definition of this disorder have since been modified.
Firenze, Italy (R Guerrini MD); disorders to manage, both for the general or paediatric The syndrome was further delineated between 1966 and
Leitender Arzt, Klinik für
Neuropädiatrie und
neurologist and for specialists in epilepsy. 1972 and a definition of LGS was proposed by Beaumanoir7
Neurologische Rehabilitation, The cause, history, types of seizures that progressively and adopted by the International League Against Epilepsy
Epilepsiezentrum für Kinder enrich the clinical picture, and specific electroencephalo- Classification Commission in 1989.8
und Jugendliche, Vogtareuth,
graphic (EEG) features are not pathognomonic for LGS,
Germany (G Kluger MD);
Epilepsy Institute of Virginia, which makes a diagnosis difficult, particularly at onset. Problems with the definition
Department of Neurology, There is no biological marker of LGS available as yet The term LGS is often loosely used to denote severe
Virginia Commonwealth and the many causes that are associated with the epilepsy syndromes of childhood featuring several types
University of Richmond, USA
syndrome complicate the assessment of the disorder of intractable seizures, including falls. However, such a
(J M Pellock MD); Institute of
Neurology IRCCS C Mondino and the treatment protocols for trials. More than ten broad definition encompasses several types of epilepsy,
Foundation and Clinical new antiepileptic drugs have been recently developed including some of the epilepsy disorders that have
Pharmacology Unit, University and might improve outcomes for patients with LGS; predominantly myoclonic-astatic seizures, for which the
of Pavia, Pavia, Italy
however, these various options make treatment choices outcome and therapy can differ.9
(E Perucca MD); and University
of Tennessee Health Science difficult. The nosological uncertainty is accentuated by the fact
Center, Memphis, USA In this Review, we describe the main electroclinical that the core seizures (ie, tonic, atonic, and atypical
(J W Wheless MD) features of LGS, discuss several topics that are still absences) are not always present at onset and the
Correspondence to: debated with regard to the definition of the syndrome, interictal EEG pattern of slow spike-waves that is
Alexis Arzimanoglou, Sleep and
compare data that are available from drug trials, and associated with LGS is not pathognomonic. In addition
Paediatric Neurophysiology
Department and Institute for present a consensual approach for optimum global to the types of seizures that are more commonly
Children and Adolescents with management of the disorder. There is a need for further associated with the syndrome, other types of seizures
Epilepsy–IDEE, HFME, University trials and new drugs for the early treatment of LGS to (eg, focal or myoclonic) and other EEG features can occur.
Hospitals of Lyon, 59 Boulevard
be unanimously accepted by the epilepsy community. A substantial proportion of cases evade precise
Pinel, 69677, Bron, France
alexis.arzimanoglou@chu- We emphasise some of the issues that, in our view, classification and the differentiation lies upon the
lyon.fr would improve the design of such further trials. quantitative proportions of the various types of seizures

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


Review

and EEG interictal abnormalities rather than on the


specific features.9 Studies on the prognosis of patients Panel 1: Summary of electroclinical features and progression of LGS
with LGS, the inclusion criteria for drug trials, and the Onset
results obtained usually indicate the above-mentioned • Usually before the age of 8 years. Occurrence rates peak between 3 and 5 years of age,
nosological uncertainties. Another factor that needs to be although late cases in early adulthood have been reported
taken into account is aetiological heterogeneity. Given • In young children with no obvious recognised cause (ie, cryptogenic), LGS usually
the poor prognosis of this syndrome for seizure control begins with episodes of drop attacks, followed by other types of seizures
and cognitive development, the term LGS should be • The full clinical picture can also gradually develop after infantile spasms and West
applied with caution. The distinction of obligate clinical syndrome
and EEG features from associative features helps to • Interrictal EEG when the patient is awake is usually abnormal from the onset of the
distinguish LGS from other epilepsy disorders that have syndrome. Reactivity of background rhythms might be conserved; these rhythms are
different prognoses. usually slow and poorly organised for the age of the child. EEG patterns when asleep
can be normal at this stage
Identification of the syndrome • Cause is heterogeneous. Brain damage (focal or multifocal abnormalities of cortical
The classic LGS triad, when the syndrome is fully development, tuberous sclerosis, and, less commonly, acquired destructive lesions or
developed, comprises many types of seizures that include metabolic diseases) plays a major role, whereas genetic factors are regarded to be less
tonic seizures, mental retardation, and an interictal EEG important
pattern of diffuse, slow spike-wave complexes (panel 1). • Neurological symptoms can be absent, depending on the underlying cause
Some authors7 consider the presence of fast (10 Hz) • Psychomotor development at the time of first seizures seems normal or the child
rhythms that are associated with the tonic attacks or that might present with a homogeneous delay in development (of varying degrees) with
occur with minimal manifestations, particularly during or without signs of a personality disorder
non-REM sleep, an essential criterion. The diagnosis of
LGS is dependent on the interaction between the clinical State period*
features and the EEG features. • Several seizure types: tonic seizure is the characteristic, prerequisite type of seizure
associated with LGS; atypical absences are associated with a decrease in consciousness;
Seizure types atonic or astatic types are characterised by abrupt falls and are usually associated with
Tonic seizures a loss of consciousness; other seizure types that might occur include myoclonic,
Tonic seizures are the most characteristic type of seizure partial, or generalised tonic-clonic, although these are seen less frequently
in LGS1,10 and their presence is a prerequisite for the • Episodes of non-convulsive status: these episodes are commonly characterised by the
diagnosis of this syndrome. However, the reported alternation of tonic attacks and episodes of confused behaviour, frequently with erratic
occurrence of this type of seizure varies: a higher incidence myoclonic activity of the face and upper limbs, which can last for hours to weeks
has been found in published series of patients in whom • Characteristic EEG abnormalities: these abnormalities are bursts of diffuse slow spike-
recordings of sleep were systematically obtained. Tonic waves at 2–2·5 cycles/s in the interictal EEG when the patient is awake or bursts of fast
seizures are not necessarily present at the onset of LGS rhythmic waves and slow polyspikes and generalised fast rhythms at about 10 cycles/s
and the age of the patient at inclusion in a series could be during sleep
another factor that might explain these variations in • Developmental delay: this delay increases with time, with a clear loss of skills and,
occurrences. Tonic refers to “a sustained increase in often, with the presence of psychotic symptoms
muscle contraction lasting a few seconds to minutes”.11 Evolution
This might be limited to a flexor movement of the head • LGS is a chronic disorder. Epilepsy, although less active, remains untreatable. The
and trunk with apnoea occasionally preceded by a brief cry intellectual and psychological deficits tend to worsen
(axial subtype) that is associated with abduction and • The EEG recording when the patient is awake remains replete with slow spike-waves
elevation of the limbs, which usually involves the arms and the EEG recording when asleep with rapid rhythms
with clenching of fists (axorhizomelic); or might affect
most muscles (global tonic attacks) and the distal parts of EEG=electroencephalogram. LGS=Lennox-Gastaut syndrome. *The clinical picture remains relatively stable in comparison to
the onset period.
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 principal clinical manifestation of a brief loss or lapse of
differential diagnosis with atonic (or even myoclonic) consciousness. These seizures are difficult to identify
seizures. There are also subtle variations in tonic seizures because of their gradual onset and termination in patients
that only comprise, for example, a slow rolling upward of whose diminished cognitive abilities might already limit
the eyes. In these cases, the use of polygraphy, including their responsiveness.
surface electromyography recording, is particularly useful. Seizures with a different underlying pathophysiology
can manifest clinically as a “pseudo absence”, including
Atypical absences complex partial seizures, seizures associated with
Atypical absences1,10 are the second most common type of generalised spike-waves on EEG, and seizures with other
seizures. This is a term used for any seizure that has a EEG characteristics that make them difficult to classify.13,14

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Review

A common occurrence of atypical absences and the many seizures usually occur in the later stages of LGS but can
other types of seizures seen in patients with LGS might sometimes precede the core attacks, which further
indicate widespread brain pathology. complicates differential diagnosis.

Sudden tonic or atonic falls Learning disabilities


Sudden tonic or atonic falls (“drop attacks”) are A variable degree of learning disability is another important
particularly hazardous and occur in about 56% of patients component of the classic LGS triad. A small proportion of
who have slow spike-waves.10 However, drop attacks, children (10–20%) are within the accepted limits of
usually preceded by a brief myoclonic jerk, are also normality but usually have difficulties in everyday life that
observed in other epilepsy syndromes (eg, in epilepsies seem to be caused by a slowing of mental processing.
with predominantly myoclonic-astatic seizures) that do Many patients (20–60%) already have delayed development
not necessarily evolve to LGS. Therefore, the presence of at onset of LGS15 and there are neurological signs or
drop attacks is not diagnostic for LGS. abnormalities in neuroimaging that are usually associated
with this syndrome (secondary or symptomatic cases). In
Non-convulsive status epilepticus cryptogenic cases (30%), the development of the child
Between 50% and 75% of patients with LGS have episodes seems normal before the appearance of the first seizures.
of non-convulsive status epilepticus, which usually The proportion of patients who have cognitive impairments
consist of subcontinuous atypical absences with varying increases to 75–95% by 5 years from onset of the
degrees of altered consciousness that are periodically syndrome.16,17 The deterioration is self-limited and is not
interrupted by recurring brief tonic seizures.9 associated with the appearance of other neurological signs
and symptoms. There have been few longitudinal
Myoclonic seizures neuropsychological studies and those done usually have
Myoclonic seizures occur in many generalised epilepsy poor statistical power. However, the epileptic activity is
syndromes and should be thought of as associated features likely to play a part in the mechanism of the difficulties in
but not as defining features.9 These seizures are shorter cognition and behaviour. Psychiatric disorders and
(<100 ms) than tonic events11 but can also lead to falls. behavioural disturbances might also be associated with the
global epilepsy syndrome (ie, LGS).
Other types of seizures
In addition to the core seizures of LGS, other types of EEG features
attacks (eg, focal seizures with or without secondary The classic EEG feature of LGS—the slow spike-wave
generalisation, tonic-clonic generalised seizures, and pattern that was originally known as the petit mal
unilateral clonic seizures) are common. These types of 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
EOG
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
L Delt 3 Hz spike-wave discharges, which are usually associated
Fz–Cz with a clinical change if their duration is longer than 3 s.
PNO In addition, photic stimulation in patients with LGS
100 μV typically fails to “activate” slow spike-waves, which
1s
distinguishes LGS from some myoclonic epilepsies.
Figure 1: EEG recording from a 12-year-old girl with bilateral perisylvian polymicrogyria and LGS Bursts of diffuse or bilateral fast rhythm patterns (10 Hz
Tonic seizure recorded during sleep. Interictal generalised slow spike-wave and wave discharges precede a tonic or more) or “polyspikes”, also called generalised
seizure, which is characterised electrographically by high-amplitude fast rhythms that last about 10 s. During the paroxysmal fast activity, are recorded during slow sleep
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
(figure 1). These bursts last for a few seconds but tend to
complexes. EEG=electroencephalogram. EOG=electro-oculograph. Fz–Cz=fronto–central midline EEG recording. recur at brief intervals18,19 and are almost identical, but
L Delt=left deltoid. LGS=Lennox-Gastaut syndrome. PNO=recording of respiration. shorter, to the bursts commonly seen in clinical tonic

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


Review

seizures that have a “recruiting” rhythm—an initial on sleep recordings. The course of the disorder in these
lowering of amplitude followed by a gradual increase in patients is characterised by active periods with multiple
amplitude (recruitment). Although these patterns might falls separated by almost seizure-free intervals that can
seem to have no clinical correlate, polygraphic recordings last several months. Recording of episodes of “continuous
can identify a brief apnoea or a mild electromyographic spike-waves of slow sleep” usually enable differential
axial contraction; therefore, a recording of non-rapid-eye- diagnosis of LGS at an early stage of the disorder. Moreover,
movement sleep might be needed to indicate their tonic seizures and generalised paroxysmal fast activity do
presence. Generalised paroxysmal fast activity occurs not occur in these patients. Patients with atypical benign
more commonly in patients with LGS (79%) than in partial epilepsy are important to distinguish because this
patients who have slow spike-waves as a result of focal type of epilepsy typically remits by adolescence.
epilepsies with secondary bilateral synchrony (15%), and Focal and secondarily generalised seizures that
this can be used to discriminate between the two.20 originate in the frontal lobe can also produce bilateral
tonic features, although these are usually asymmetrical
Diagnostic issues and differential diagnosis early in the seizure (Blume WT, personal communication).
The diagnosis of LGS depends on the combination of the Furthermore, these patients will sometimes have EEG
electroclinical criteria as defined above. The predominance recordings that show generalised spike-wave discharges
of tonic seizures and patterns of fast rhythms are probably as a manifestation of rapid spread across the corpus
the most indicative features of the syndrome. However, callosum (secondary bisynchrony). The possibility of
these features are not necessarily present at onset, many secondarily generalised seizures should be taken into
other types of seizures can appear first, tonic seizures are account if the neurological examination, interictal or ictal
not always easy to detect, and an EEG recording during EEG recording, or neuroimaging scan show relevant
sleep might be mandatory. The clinical presentation of lateralised abnormalities.
LGS remains heterogeneous and the multiple causes that In summary, the diagnosis of LGS depends on a
can be associated with the syndrome can also affect conjunction of clinical and EEG abnormalities. There is a
prognosis or sometimes therapeutic strategies. risk for underdiagnosis because some types of seizures
Attention to the criteria defined above for diagnosis of might occur many months before the initial appearance
LGS should remove from consideration many similar of slow spike-waves1,10 and EEG recordings of sleep are
disorders in most patients. However, as with any epilepsy not always available. However, because EEG recordings
disorder, the boundaries between syndromes might be during sleep are required for the diagnosis of LGS, these
blurred. For example, infantile spasms and hypsarrhythmia should be made available to the clinician during
can gradually progress to LGS with slow spike-waves, diagnosis. Conversely, there is also a risk for overdiagnosis
which accounts for about 20% of all cases of LGS.21 of LGS: a diagnosis for this syndrome should not depend
Distinctions between a long spasm (>1 s) and a short only on the presence of slow spike-wave discharges on
tonic seizure can be arbitrary,1 but the tendency of spasms EEG recordings; furthermore, patients with only tonic
to cluster might help to distinguish between the two types seizures or drop attacks do not necessarily meet the
of seizures. Among patients who present between the ages criteria of LGS.
of 2 and 5 years, seizures at onset might be prominently
myoclonic or myoclonic-astatic, there might be episodes of Management issues
non-convulsive status epilepticus, and the EEG recording Results of trials
might variably feature fast spike-wave complexes and slow Randomised controlled trials have been done in patients
spike-wave complexes,22 which suggests the clinical picture with LGS to study the effects of lamotrigine, topiramate,
characterised as Doose’s syndrome. In a second phase of felbamate, rufinamide, an analogue of thyrotropin-
evolution, some of these patients will develop tonic seizures releasing hormone, and cinromide (table 1).26–30 A
and a picture that fulfills the main criteria for LGS.9 Cochrane review of randomised controlled trials of
Differential diagnosis at onset is difficult in the absence of treatments of LGS concluded that lamotrigine,
biological markers, particularly for cryptogenic cases.23 topiramate, and felbamate might be helpful as add-on
However, other epilepsy syndromes with an early onset in therapies for patients with this syndrome.31 A decrease in
childhood (eg, early-onset childhood absence epilepsy or the frequency of all seizures was found for patients taking
Dravet’s syndrome) differ from LGS in initial clinical lamotrigine compared with placebo (–32% vs –9%;
presentation, course, prognosis, and therapy, and should p=0·02)28 and felbamate compared with placebo (–19% vs
not be confused with LGS. Some examples of EEG +4%; p=0·002),27 whereas the decrease in total seizure
abnormalities that might be clinically confused with LGS frequency for topiramate did not reach statistical
are shown in figure 2. significance (–21% vs –9%).29 The frequency of drop
A more difficult problem for diagnosis is atypical benign attacks decreased significantly after lamotrigine28 or
partial epilepsy,17,24 which is also known as pseudo-Lennox topiramate.29 Felbamate significantly lowered the
syndrome.25 Children with atypical benign partial epilepsy frequency of atonic seizures;27 the term “atonic seizures”
present with multiple falls and diffuse EEG abnormalities was probably used to indicate drop attacks in that study.

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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.

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

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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

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Review

success.65 Patients with LGS have a larger variability in A ketogenic diet can improve seizure control for some
their pharmacokinetic response than other populations patients with LGS. The atonic and myoclonic seizures
with other forms of epilepsy, partly because of age and associated with LGS decreased rapidly by more than 50%
partly because of their frequent polytherapy.66 Despite in children on a ketogenic diet.84
evidence that the pharmacokinetics of most antiepileptic Preliminary results with electrical stimulation of the
drugs are different in young children compared with centromedian thalamic nucleus have also been reported
adults,67 there are limited data on how the pharmaco- for generalised seizures.85 The overall frequency of
kinetics of antiepileptic drugs vary according to age, seizures was reduced by 80% in 13 patients with LGS and
bodyweight, and body surface area. Drug interaction a subsequent improvement in independence of patients
data from adults might also not be readily extrapolated and a decreased dependence on caregivers was seen.85
to children because of age-related changes in drug Although some of the results of these studies are
metabolism and patterns of co-medication exposure. promising, these data are difficult to interpret because of
Failure to compensate for major pharmacokinetic the uncontrolled design of the trials and, in many studies,
changes could result in underdosing or overdosing; concurrent changes in associated antiepileptic drug
therefore, more pharmacokinetic studies of antiepileptic therapies.
drugs in paediatric populations are needed.
More data are also needed to discern the association Treatment considerations: global assessment and
between serum drug concentration and clinical response.68 outcome
Optimum responses to antiepileptic drugs are obtained at Seizures are not the only manifestation of many epilepsy
different serum drug concentrations in different patients syndromes, and the associated comorbidities are of
and are dependent on the type of seizure and epilepsy concern, particularly the effects on behaviour and
syndrome;69 therefore, studies in patients with LGS are cognition. This is specifically the case for LGS, in which
needed. Responsiveness to the concentration of a particular patients are not only impaired in their everyday lives by
antiepileptic drug, including adverse effects, can also be drop attacks that are often frequent, difficult to treat, and
affected by age and co-medication.65,70 Characterisation of can cause injury, but also by impairments in cognition
the concentrations associated with optimum responses in and behaviour. These cognitive and behavioural
individuals (and an analysis of the covariates that are impairments are often difficult to quantify in the short
implicated) could improve the clinical management of and long term but need to be considered when comparing
these patients.70–72 one treatment with another.
Contrary to the conventional management of epilepsy,
Non-pharmacological management the aim of treatment of LGS is often to suppress or
Complete or partial callosotomy is the primary palliative reduce the frequency of the more disabling types of
surgical treatment for children with LGS who have seizures rather than complete freedom from seizures
frequent seizures that cause drop attacks. Complete (although this would be the ultimate aim). The more
resection will probably lead to fewer drop attacks; complex aspects of LGS, such as the occurrence of non-
however, complete resection is not always technically convulsive status epilepticus or the effects of the epilepsy
possible. The effect of total or partial corpus callosotomy syndrome on cognition and behaviour compared with
on cognitive functioning, social adjustment, and motor the effects of the medication are difficult to quantify over
behaviour needs to be studied further, particularly if this a short response time to treatment. Many of these
procedure is to be used in children with only moderate problems are not assessed in short-term clinical trials,
cognitive impairment.73–75 Callosotomy has been which typically measure efficacy over only 10–16 weeks.
associated with improved control of atonic or tonic The age range is also broad and, owing to the progression
seizures, although lower success rates have been reported of the syndrome and the different expectations at
for generalised tonic-clonic seizures.76–78 different ages, the aims for benefit in treatment might
Stimulation of the vagus nerve might also help in the differ in accordance with the stage of the disease. For
treatment of drop attacks. This treatment has a lower example, newly diagnosed children might have had a
morbidity risk than callosotomy does and has also been catastrophic onset of epilepsy with developmental arrest;
used as an adjunct to the callosotomy procedure.79,80 the aims of therapy in such a case would be to reverse, at
Several open, prospective trials have assessed the response least in part, the cognitive impairment and behavioural
of patients with LGS to stimulation of the vagus nerve. abnormalities of the child. However, in an older child,
After 6 months of vagus nerve stimulation, a median who might have had several years of treatment, the
reduction in total seizure frequency of 46–58% was expectations might be reduced frequency of seizures
reported,81,82 whereas atonic seizures decreased by 88%.82 rather than specific changes in cognition. Improved
The long-term follow-up of vagus nerve stimulation in control of seizures can result in greater alertness, which
children with LGS has indicated no adverse effects in might translate into altered behaviour of the patient;
behaviour, and positive changes in behaviour were noted this change could potentially be misunderstood as a
in some patients.83 behavioural side-effect of the treatment.

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Review

Because seizures in LGS tend to be resistant to treatment, research studies in LGS. Functioning of the patient in
seizure reduction should not be pursued at all costs. It is the ICF model is described as the dynamic interaction
not uncommon for the patient’s quality of life to be among three dimensions: body functions or structures;
impaired more by the side-effects of treatment than by the activity and participation; and environmental factors.
seizures themselves. Physicians should always be vigilant This is now widely internationally used in rehabilitation
for adverse drug effects, particularly on coordination, outcome research, and the use of this model in the
cognition, and behaviour, and should not increase doses assessment of patients with LGS is a challenge. An
or the number of drugs when considerable adverse effects example of global assessment using the ICF model is
are already present. In some cases, excessive drug loads shown in table 2. However, the ICF model was developed
can paradoxically increase the frequency of seizures, which for the assessment of stable disorders such as
can result in more aggressive treatment and thus further psychomotor disabilities; therefore, the application of
increase the severity of seizures.54 this model for the assessment of paroxysmal disorders
Agreement of written treatment goals with parents, such as epilepsy will need thorough investigation.
caregivers, and the patient, if possible, could be made
before selecting a treatment plan. A global outcome Methodological issues for future trials
assessment can then be measured in accordance with the In the past decade, a formalised clinical trial strategy has
treatment plan for each patient. Assessments of the quality been devised for the study of the therapeutic effects on
of life are more important in the long term than LGS on the basis of the substantial treatment effects of
measurements of seizure outcome. Therefore, the felbamate, lamotrigine, topiramate, and rufinamide
management of patients with LGS and any consideration (table 1).26–30
of the effect of a new treatment has to account for all The difficulty in characterising LGS makes the design
aspects of quality of life, and any study of efficacy has to of clinical trials of this disorder difficult. Most types of
ideally measure change during an appropriate length of seizures can be frequent and the ability to determine the
time. Such measurement is difficult in placebo-controlled, onset, duration, and eventual repetition of individual
add-on studies because of ethical reasons; these studies events correctly, compared with prolonged seizures, is
usually have a maximum duration of placebo treatment of sometimes nearly impossible. Often, only the most
4 months as cognitive and behavioural regression might severe seizures, such as those that cause drop attacks, are
proceed during longer placebo periods. However, active the ones that can be recorded easily. Postictal lethargy
control trials, which might have a longer duration, could and confusion might also be impossible to distinguish
be done in the future. Ideally, the outcome assessment clinically from atypical absence seizures, even with
should be undertaken over no less than 6 months. constant observation; constant monitoring might only
Another way to enable assessments over the long term just be achieved with video EEG recording. Nocturnal
would be to use standardised measures of cognitive tonic seizures, although sometimes frequent, might not
performance and behaviour. Specific subtests of be as easy to identify as ictal events, even with EEG
standardised scales could provide a means to monitor monitoring over 24 h. The problems encountered in the
specific aspects of cognition. A further possibility would trial of cinromide is one example of the difficulty of doing
be to use the International Classification of Function, studies in which all daily seizures are counted:26 in this
Health, and Disability (ICF)86 to plan intervention and trial, no difference in seizure frequency was seen between

Dimensions of ICF 4-year-old patient 12-year-old patient 35-year-old patient


Body functions and • Do the causes of LGS alone predict mental retardation and • Can there be a further effect on cognition • Can better control of seizures result in improved mental
structures other neurological disorders or can seizure control prevent with improvement in seizures? or behavioural functions?
cognitive or behavioural decline? • Is freedom from seizures possible? • Is freedom from seizures still possible?
• Is freedom from seizures possible? • What is the effect of medication on • Do antiepileptic drugs that failed in the past now have a
• What is the effect of medication? behaviour or cognition? different effect?
• Does control of seizures contribute to paradoxical change • Does control of seizures contribute to paradoxical change
in behaviour? in behaviour?
Activity and • Pre-school education • Integration and schooling • Self-independence
participation • Injuries • Relationships with peers • Mobility
• Interaction with peers • School trips • Working
• Out-of-school activities • Social interaction
Environmental • Burden on the family with brothers and sisters • Attitude of school • Living outside the family
factors • Parental employment • Burden on the family • Partnership
• Residential schooling? • Risks of sudden unexpected death?
• 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 www.thelancet.com/neurology Vol 8 January 2009


Review

the treatment and placebo groups, possibly because


parents could not distinguish seizures from other Search strategy and selection criteria
behavioural activities. References for this Review were identified through searches of
Other problems in the design of clinical studies in LGS PubMed by use of the search terms “aetiology”, “antiepileptic
relate to the criteria for enrolment, which should be drugs”, and “Lennox-Gastaut syndrome” in combination with
consistent with the definition of LGS. Entry criteria for “diagnosis”, “EEG”, “slow spike waves”, and “randomised
specific EEG characteristics must be clearly defined and controlled trial”, between January, 1950, and August, 2008.
should be standardised among study centres. The All randomised controlled trials of LGS were included in this
provision of definitions for types of seizures and Review. Only papers published in English, French, and German
specifications for the number and type of concurrent were reviewed. The final reference list was generated on the
therapies and rescue therapies allowed during the course basis of relevance to the topics covered in this Review.
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 interictal slow spike-waves, spikes and bursts of 10–20 Hz
should also be considered. spikes during sleep, and impairments in cognition. The
The duration of epilepsy before enrolment in a clinical core types of seizures (ie, tonic and atonic, atypical
trial can also be crucial. At onset, LGS has some of the absences, and episodes of non-convulsive status
characteristics of a progressive disorder (ie, the epilepticus) can be variably associated with attacks that are
appearance of new types of seizures, deterioration of the thought to be less characteristic, such as tonic-clonic,
interictal EEG recording, and an effect on cognitive partial, or unilateral seizures. However, early diagnosis can
development). Consequently, LGS is commonly suspected be difficult, and an early referral to an epilepsy specialist is
but not actually confirmed. Additionally, the effect of important because not all indicators of LGS are present at
drug treatment might be different in patients who onset and none of the typical features are pathognomonic.
progress to the later stages of LGS than in patients who Despite the availability of several new antiepileptic
have had a more stable form of the disorder for longer. drugs, which have been validated through well-designed,
The identification of antiepileptic drugs that can stop the randomised, controlled trials for the treatment of drop
progression of the syndrome towards an epileptic attacks in LGS, this disorder is still one of the most
encephalopathy would be welcomed. Current trials can challenging epileptic encephalopathies to the treating
assess the ability of a new drug to stabilise the disorder physician, the companies that design clinical trials and
only when it has already reached a devastating plateau. The develop therapies, the regulatory authorities, and, of
acceptance of broader enrolment criteria and the long-term course, to the patients and their families.
identification of “pure” or “incomplete” LGS would provide A more holistic approach to the investigation of the
us with results that are more clinically meaningful. effects of newer medications might help to identify
Novel endpoints and measurements for improvement treatments that, when used in the early stages of the
instead of a reduction in seizures (eg, effects on cognition, disorder, might have long-term beneficial effects on
behaviour, and quality of life) should also be investigated. seizures and the associated comorbidities.
Quality-of-life measures tailored to LGS and consideration Contributors
of different aspects of an individual’s epilepsy (eg, severity AA participated in the preparation of the first draft of the Review,
of seizures, concurrent seizures, duration of seizures, discussed contributions from all co-authors, and approved the final
version. JF participated in the writing and editing of the Review. WTB
and number of days without drop attacks) might be participated in the section on the concerns for diagnosis and differential
useful indications of the actual everyday benefits of a diagnosis. JHC participated in the discussion, writing, and final editing
treatment. Specific strategies should also be sensitive of the Review and prepared the section on treatment considerations with
enough to detect worsening—or improvement—of regard to outcome. J-PE participated in the section on non-
pharmacological treatments. MF participated in the meeting that formed
different types of seizures. 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
Conclusions provided publications that were used in the drafting of this Review. RG
Given the need to develop further therapies for patients 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
with LGS, the orphan drug designation procedure in the the writing and reviewing of the Review. JMP participated in the writing
USA is a practical approach that encourages the devel- and editing of the Review. EP and JWW participated in the writing of the
opment of drugs for the treatment of severe and rare Review.
disorders, such as LGS. Although orphan drug status is not Conflicts of interest
a marketing authorisation, this approach encourages the AA has received speaker payments, consultancy fees, and/or research
development of drugs that are necessary for the treatment grants from Cyberonics, Eisai, GlaxoSmithKline, Johnson & Johnson,
Novartis, Pfizer, Sanofi-Aventis, Schwartz Pharma, UCB Pharma, and
of rare diseases but that would be prohibitively expensive or Valeant. JF has consulted on behalf of Eisai, but received no personal
unprofitable to develop under normal circumstances. income. Consulting fees have been accepted by either the Epilepsy Study
Diagnosis of LGS is not difficult if strict criteria are used: Consortium or the Department of Neurology at the University of
Pennsylvania. The total amount was US$<10 000. JF has spoken on
several types of seizures (including tonic seizures),

www.thelancet.com/neurology Vol 8 January 2009 91


Review

behalf of Eisai in satellite symposia at international epilepsy meetings in 12 Gastaut H, Broughton R. Tonic seizures. In: Epileptic seizures.
2007 and 2008: the honoraria from these went to the Department of Springfield, Illinois: CC Thomas, 1972: 37–47.
Neurology at the University of Pennsylvania, and the New York Epilepsy 13 Andermann F. Absences are non-specific symptoms of many
and Neurology PLLC, respectively. In both cases, travel to the speaking epilepsies. In: Wolf P, ed. Epileptic seizures and syndromes.
events was reimbursed. JHC has received honoraria and educational London: John Libbey, 1994: 127–31.
grants from Janssen Cilag, UCB Pharma, Eisai, and SHS International. 14 Henriksen O, Dreifuss FE. Currently unclassifiable seizures.
J-PE has received speaker payments, consultancy fees, and/or research In: Engel J Jr, Pedley TA, eds. Epilepsy, a comprehensive textbook.
grants from Eisai, Janssen Cilag, Novartis, Sanofi-Aventis, UCB Pharma, Philadelphia: Lippincott-Raven, 1997: 665–67.
and Desitin. MF has received consultation, advisory board, and speaking 15 Beaumanoir A, Blume W. The Lennox-Gastaut syndrome.
honoraria from Eisai, Gerot Pharmaceuticals, GlaxoSmithKline, Jannsen In: Roger J, Bureau M, Dravet C, et al, eds. Epileptic syndromes in
Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB Pharma, and Cyberonics. infancy, childhood and adolescence, 4th edn. Paris: John Libbey,
2008: 125–48.
JMP has received speaker payments, consultancy fees, and/or research
grants from the National Institutes of Health, the National Institute of 16 Livingston JH. The Lennox-Gastaut syndrome. Dev Med Child
Neurol 1988; 30: 536–40.
Neurological Disorders and Stroke, Abbott Laboratories, AstraZeneca,
Aventis, Cephalon, Eisai, GlaxoSmithKline, Jazz Pharmaceuticals, 17 Aicardi J, Chevrie JJ. Atypical benign epilepsy of childhood.
Dev Med Child Neurol 1982; 24: 281–92.
King Pharmaceuticals, KV Pharmaceuticals, Marinus Pharmaceuticals,
18 Blume WT, David RB, Gomez MR. Generalized sharp and slow
MedPointe, Neurpace, Novartis, Ortho-McNeil, Johnson & Johnson,
wave complexes—associated clinical features and long-term follow-
Ovation, Pfizer, Questcor, Schwarz Pharma, UCB Pharma, and Valeant.
up. Brain 1973; 96: 289–306.
EP has received speaker payments, consultancy fees, and/or research
19 Blume WT, Kaibara M. Atlas of pediatric electroencephalography.
grants from Bial, Cyberonics, Eisai, GlaxoSmithKline, Johnson &
New York: Lippincott-Raven, 1999.
Johnson, Novartis, Ovation, Pfizer, Sanofi-Aventis, Schwartz Pharma,
20 Gastaut H, Zifkin BG. Secondary bilateral synchrony and
SK Holdings, UCB Pharma, and Valeant. JWW has received grants and/
Lennox Gastaut syndrome. In: Niedermeyer E, Degen R, eds:
or speaker payments and/or consultancy fees from the National The Lennox Gastaut syndrome. New York: Alan R Liss, 1988: 221–42.
Institutes of Health, Shainberg Foundation, Abbott, UCB Pharma, 21 Genton P, Guerrini R, Dravet C. The Lennox-Gastaut syndrome.
GlaxoSmithKline, Ovation, Questcor, Marinus, Ortho-McNeil, In: Handbook of clinical neurology (vol 73): the epilepsies. Part II.
King Pharmaceuticals, Cyberonics, Novartis, Pfizer, Eisai, Shire Meinardi H, ed. Amsterdam: Elsevier, 2000: 211–22.
Pharmaceuticals, Valeant, Cydex, and Neurelis. WTB, PG, RG, and GK 22 Hoffmann-Riem M, Diener W, Benninger C, et al. Nonconvulsive
have no conflicts of interest to declare. None of the authors received status epilepticus—a possible cause of mental retardation in
financial support or honoraria for the preparation of this paper. patients with Lennox-Gastaut syndrome. Neuropediatrics 2000;
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Acknowledgments
All authors of this Review participated in an expert consensus meeting 23 Kaminska A, Ickowicz A, Plouin P, et al. Delineation of cryptogenic
Lennox-Gastaut syndrome and myoclonic astatic epilepsy using
on LGS funded by Eisai Europe. The discussions raised at this meeting
multiple correspondence analysis. Epilepsy Res 1999; 36: 15–29.
formed the basis of this Review. The first draft of the paper was prepared
24 Aicardi J. Atypical semiology of rolandic epilepsy in some related
by AA and then given to all authors for specifc contributions on the basis
syndromes. Epileptic Disord 2000; 2: S55–59.
of their specialist field. AA also used a summary of the meeting that was
25 Hahn A. Atypical benign partial epilepsy/pseudo-Lennox syndrome.
produced by a medical writer (ACUMED) at the request of Eisai. The
Epileptic Disord 2000; 2: S23–28.
sponsor had no part in the content of this Review. The authors thank
26 The Group for the Evaluation of Cinromide in the Lennox-Gastaut
K de Saram at Complete Medical Communications who provided
syndrome. Double-blind, placebo-controlled evaluation of
editorial assistance. cinromide in patients with the Lennox-Gastaut syndrome. Epilepsia
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