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Current thumbnail: Lennox-Gastaut syndrome comprises the combination of tonic seizures that mainly occur in sleep, atypical absences and slow spike-waves, with cognitive deterioration. Drop attacks are a cosquence of both tonic seizures and atypical absences. The condition may follow West syndrome or complicate focal epilepsy (although this is rare if the latter was not preceded by West syndrome) or occur de novo, as a symptomatic or cryptogenic condition.

Historical note and Nomenclature
An EEG with a 2 Hz ("slow") spike-and-wave pattern was first described in 1939 (Gibbs et al 1939). It was associated with a special type of absence seizure characterized by incomplete loss of consciousness. By contrast, classic petit mal absence seizures had been known to be associated with rhythmic 3 Hz spike-and-waves. The term "petit mal variant" was therefore used to describe the EEG pattern and the clinical seizure complex (Gibbs et al 1948).

Lennox and Davis first correlated the slow spike-and-wave EEG pattern with a distinctive group of clinical manifestations (eg, mental retardation and specific seizure types), including myoclonic jerks, atypical absences, and astatic seizures (drop attacks) (Lennox and Davis 1950). Gastaut and his colleagues described the clinical manifestations and EEG patterns of 100 patients with slow spikes-and-waves (Gastraut et al 1966). They called this syndrome "Lennox syndrome" or "childhood epileptic encephalopathy with diffuse slow spike-and-waves." The term "Lennox-Gastaut syndrome" first appeared in the literature in 1969 (Niedermeyer 1969). The International Classification of Epilepsies, Epileptic Syndromes, and Related Seizure Disorders classifies the Lennox-Gastaut syndrome as a cryptogenic or symptomatic generalized epilepsy (Anonymous 1989).

The concept of the myoclonic variant of Lennox-Gastaut syndrome was developed in the late 1980s (Aicardi 1995), but there is growing evidence that these patients are affected by the severe form of myoclonic-astatic epilepsy identified in the early 1970s (Doose 1985), thus illustrating the difficulties in distinguishing both conditions (Dulac et al 1998). Previous clinical descriptions differentiated these syndromes--myoclonic-astatic epilepsy rarely being identified as an exclusion criteria or a differential diagnosis.

Clinical manifestations
The Lennox-Gastaut syndrome may result from a variety of diffuse encephalopathies. It is characterized by the clinical triad of diffuse slow spikes-and-waves on EEG, mental retardation, and multiple types of generalized seizures, including especially atypical absences and tonic and atonic seizures (Beaumanoir 1985; Niedermeyer and Degen 1988; Aicardi and Levy Gomes 1992; Dulac and N'Guyen 1993). The Lennox-Gastaut syndrome is, with rare exception, a condition of children. The age of onset is between 2 and 8 years in most cases. Boys are affected more frequently than girls. Symptoms can appear de novo without apparent cause (cryptogenic Lennox-Gastaut syndrome) or result from obvious brain insult (symptomatic Lennox-Gastaut syndrome). Cryptogenic cases start later than symptomatic cases do.

In young children, the Lennox-Gastaut syndrome usually begins with episodes of sudden falls. In the school-age group, behavioral disturbances may be the heralding signs, along with drop attacks. This is soon followed by frequent seizures, episodes of status epilepticus, progressively deteriorating intellectual functions, personality disturbances, and chronic psychosis (Roger et al 1989).

Tonic seizures occur in most affected children. They are usually brief, lasting only seconds. Depending on the extent and groups of muscles involved, they may appear as axial (characterized by flexor movements of the head and trunk), axial rhizomelic (characterized by elevation and adduction of proximal upper limbs, stiffening of posterior neck muscles, elevation of shoulders, opening of the mouth, upward deviation of the eyes and brief apnea), or global, leading to sudden falls if the patient is in an upright position (Gastraut et al 1966). The seizures can be asymmetrical or predominantly unilateral. Sometimes automatic behaviors follow the tonic stage. Tonic seizures occur most frequently when falling asleep, but they can occur at any time of the day. They may occur subclinically and may be revealed only by a polygraphic sleep EEG tracing with simultaneous EMG recording. They may also be precipitated by stimuli such as noise, contact, or movement (Roger et al 1989).

Atypical absence seizures occur in approximately two-thirds of patients. Both the onset and the termination are gradual in contrast to the strikingly sudden lapses in typical absence. Whereas typical absences are usually brief (less than 10 seconds) and consciousness returns immediately and completely afterward, atypical absences are usually longer and are often followed by some postictal cognitive impairment. During the atypical absence there is "clouding" rather than loss of consciousness so that patients can continue their activity to some degree (Gastraut et al 1966). Associated manifestations are more common in atypical than in typical absences and include eyelid or perioral myoclonus, progressive flexion due to loss of postural tone, and localized motor phenomena, such as neck-stiffening or head-nodding (Roger et al 1989).

Atonic seizures are characterized by sudden, intense loss of postural tone that involves either the whole body or only the head (Roger et al 1989).
Other kinds of seizures, including partial and generalized tonic-clonic seizures, are less frequent (Roger et al 1989). Myoclonic seizures in which consciousness usually remains clear, enabling patients to arise without assistance promptly after falling, are rare in Lennox-Gastaut syndrome. They are a distinctive feature of myoclonic-astatic epilepsy, however (Doose 1985).

Myoclonic, myoclonic-atonic, atonic, and tonic seizures all cause falls (drop attacks) and are difficult to differentiate clinically from one another without polygraphic recording (Ikeno et al 1985). The falls result in recurrent injury, including lacerations that leave disfiguring scars (Roger et al 1989).

Most patients with the Lennox-Gastaut syndrome have 1 or more episodes of status epilepticus (Dulac and N'Guyen 1993). A variety of forms of status epilepticus occur that represent a continuum from absence status, consisting of an insidious confused state that can last for days or weeks, to pure tonic status epilepticus, which is more often seen in adolescents or adults than in children. Absence status may be difficult to recognize, particularly in children with severe mental retardation. Tonic status has been reported to be occasionally elicited by intravenous administration of benzodiazepines (Tassinari et al 1972).

In young children, slowing or even complete arrest of psychomotor development occurs. In cases of later onset, the intellectual impairment may be less pronounced than in cases of early onset (Gastaut et al 1966). In addition, behavioral abnormalities occur in half the cases, including hyperactivity (most commonly), emotional instability, aggressiveness, destructive behavior, autism, antisocial personality, or hypersexuality (Markand 1977). Such abnormalities and the arrest of educational progress are more prominent in older children and adolescents than in younger children. Chronic psychosis with episodes of acute exacerbation may also occur (Roger et al 1989; Jambaque et al 2002).

Interictal neurologic symptoms are not specific for Lennox-Gastaut syndrome, but they are determined by the location and extent of the underlying pathology. Motor signs occur in 59% of cases. Cerebellar signs may be difficult to differentiate from effects of antiepileptic drugs (Markand 1977). Seventeen percent of patients have normal neurologic examinations.

Clinical Vignette
No information was provided by the author.

Etiology
In about 30% of cases, the symptoms appear without antecedent history or evidence of brain pathology. Such cases are called "cryptogenic" Lennox-Gastaut syndrome. It is this group that is difficult to distinguish from myoclonic-astatic epilepsy. There is no evidence of a genetic predisposition even though previous studies may have reported a higher incidence of epilepsy or febrile convulsions in these patients than in the general population before the distinction between Lennox-Gastaut Syndrome and myoclonic-astatic epilepsy was made.

The other 70% of cases are "symptomatic." They are associated with preexistent brain damage, usually acquired in the prenatal or neonatal periods or in infancy. Pre and perinatal factors comprise ABO blood group incompatibility, prematurity, abnormal presentation, prolonged labor, cord prolapse, respiratory depression, and various malformations including tuberous sclerosis, porencephaly, and dysembryoplastic neuroepithelial tumor (Quarato et al 2002). With the advent of high resolution MRI, cortical dysplasias are being identified as an increasingly common substrate of the Lennox-Gastaut syndrome (Ricci et al 1992). Band heterotopia is a newly identified cause of Lennox-Gastaut syndrome (Barkovich et al 1994; Granata et al 1994). Postnatal factors include central nervous system infection, degenerative or metabolic disorders of the nervous system, head injury, anoxic encephalopathy, cerebrovascular accident, hypoglycemia, and irradiation leukoencephalopathy (Markand 1977; Mitsufuji et al 1996). An autoimmune mechanism has been proposed for some cases, but there still is little evidence to support this concept (van Engelen et al 1995).
Approximately one-third of patients with symptomatic Lennox-Gastaut syndrome represent evolution from infantile spasms, occurring in infants and young children (Gastraut et al 1966).

The age range of occurrence suggests that some maturational, yet unidentified, factor plays a determinant role in the development of Lennox-Gastaut Syndrome.

Pathogenesis and Pathophysiology
No specific pathophysiological mechanisms have been demonstrated to underlie the Lennox-Gastaut syndrome; however, the frontal lobes appear to play a predominant role in the epileptic symptoms, and the usual age of appearance of this syndrome corresponds with maturation of the frontal lobes (Dulac and N'Guyen 1993). Thus, frontal lobes are affected, one being the leader (Bonnani et al 2002). At the onset of the epilepsy, focal spike-waves and focal discharges are often recorded (Hughes and Patil 2002). There is also evidence that subcortical structures are involved in the epileptogenic process (Velasco et al 1991).

The major so-called ”interictal” spike-wave activity seems to play a major role in the development of cognitive troubles compared to the seizures themselves, which are “minor” as commonly mentioned. Lennox-Gastaut syndrome is one of the epileptogenic encephalopathies, a condition between epilepsy and status epilepticus that also comprises infantile spasms and continuous spike waves in slow sleep.

The relative role of spike waves and fast activity is probably related to the ability of neuronal network to produce slow waves that are related to GABA release and to interrupt the fast activity (Blume 2001; Halasz and Janszky 2002).

Epidemiology
Although the incidence of the Lennox-Gastaut syndrome is low, the intractable nature of this disorder accounts for a prevalence of 5% of epileptic patients of all ages and about 10% of epileptic patients under 15 years of age (Gastaut et al 1975; Heiskala 1997; Trevathan et al 1997).

Prevention
No information is available.

Differential Diagnosis
Drop attacks and slow spike-and-wave discharges on EEG may also be seen in patients who have conditions other than Lennox-Gastaut syndrome, including overdose of certain antiepileptic medication and partial seizures secondary to structural lesions. Both may produce continuous spike waves in slow sleep (Patry et al 1971). Posttraumatic epilepsies and encephalopathy with multifocal epilepsy associated with secondary generalization may produce frontal lobe epilepsy with secondary generalization of the spike-wave activity (Roger et al 1989). In these patients, the tonic seizures are usually missing, and onset is at a later age.
Three other epilepsy syndromes may produce drop attacks. Epilepsy with myoclonic-astatic seizures begins between 2 years and 5 years of age with generalized tonic-clonic seizures. This is followed, several months later, by frequent daily drop attacks due to myoclonic-astatic seizures with atypical absences (Doose 1985). The EEG reveals 2 Hz to 3 Hz spike-and-wave discharges and a slow baseline activity.

The syndrome of continuous spike-waves in slow sleep begins between 3 years and 6 years of age with atonic seizures and atypical absences with slow spike-waves, but there are no tonic seizures (Patry et al 1971).
Infantile spasms that produce drop attacks may begin between 1 year and 4 years of age. The drop attacks can be identified as the result of epileptic spasms only through video-EEG recordings of the seizures (Bednarek et al 1998).

Diagnostic Workup
The diagnosis is based on the combination of several types of generalized seizures. Tonic and atypical absences may need ictal EEG recording to be properly identified; irregular slow spike-and-waves can be identified with interictal awake tracing; whereas polyspikes-and-waves are recorded during sleep. Cognitive and behavior deterioration may be missing at onset.
The slow spike-and-wave consists of a blunt, slow spike (approximately 150 msec), followed by a slow wave (approximately 350 msec). The amplitude ranges from 200 microvolts to 800 microvolts. When 2 spikes to 3 spikes precede the slow wave, they constitute a polyspike-and-wave complex. The frequency (1.5 Hz to 2.5 Hz) is relatively slow and arrhythmic compared to that of classical absence seizures (rhythmic 3 Hz). Occasionally, bursts of rapid spike-and-waves at 3 Hz or even 4 Hz may occur in combination with the slow spike-and-waves (Gastaut et al 1966). Generalized polyspike discharges or lower voltage fast activity (generalized paroxysmal fast activity) lasting 1 second or more without obvious clinical correlates are common during slow wave sleep. Relaxation, drowsiness, sleep, and hyperventilation facilitate the appearance of slow spike-and-waves. During sleep, the abnormal patterns become more prominent, symmetrical, and synchronous, with even slower spike-and-waves or polyspikes-and-waves. Photic stimulation, on the other hand, has no effect on these EEG events (Markand 1977). When evolution in EEG patterns occurs in patients previously affected by infantile spasms, the direction is from hypsarrhythmia to multifocal interictal spikes to generalized spike discharges to slow spike-and-waves, with the last representing a stable pattern that characterizes children with the Lennox-Gastaut syndrome (Kotagal 1995).

The interictal EEG discharges are usually generalized, bilateral, synchronous, and symmetrical. But they may also be asymmetrical and predominant in 1 hemisphere or 1 region. The EEG patterns differ among individuals and change from day to day and even moment to moment (Gastaut et al 1966).

The EEG correlate of tonic seizures consists of a 10 Hz to 13 Hz recruiting rhythm, usually followed by high amplitude slow activity rather than postictal EEG depression (Dulac and N'Guyen 1993). Although the EEG during absence seizures often shows irregular spike-and-wave discharges, these patterns are not necessarily different from interictal EEG discharges and do not clearly demarcate the occurrence of an ictal event. Similarly, there is no characteristic pattern of absence status; this prolonged confused state may be associated with an increase in slow spike-and-wave activity or with irregular slowing resembling hypsarrhythmia (Dulac and N'Guyen 1993).

A variety of multifocal or diffuse abnormalities on MRI are found in the symptomatic cases, but this finding concerns etiology, not diagnosis, of the epilepsy syndrome. Drop attacks, slow spike-waves with mainly posterior predominance and cognitive deterioration, combined with brain calcifications have been reported as a consequence of gluten intolerance and can be improved by gluten-free diet (Pratesi et al 2003).

Prognosis
The prognosis is poor, and the syndrome does not evolve into a localization-related epilepsy (Yagi 1996). Remission with preserved mentation occurs in few patients; rather, IQ tends to deteriorate with age (Oguni et al 1996), and tonic seizures persist, but the slow spike-and-wave pattern does tend to resolve. Patients with underlying brain damage particularly preexistent West syndrome, early onset, frequent and slow evolution of seizures, and repeated episodes of status have a relatively worse prognosis (Roger et al 1989).

Management
The treatment of Lennox-Gastaut syndrome has been difficult and disappointing. Carbamazepine and phenytoin can control generalized tonic-clonic convulsions and reduce tonic seizures, but these drugs can also exacerbate atypical absence seizures. Valproate offers a chance for improvement of all seizure types with a single drug but soon loses its effect.
Lamotrigine has also shown a significant effect on drop attacks although atypical absences were not significantly affected (Motte et al 1997). However, this drug should be introduced slowly in patients receiving valproate in order to prevent serious rash (Dulac and Kaminska 1997).
Felbamate has been reported to reduce the frequency and severity of drop attacks (Felbamate Study Group 1993; Avanzini et al 1996) and other seizure types (Jensen 1994) and can improve behavior in some patients (Gay et al 1995). However, this drug is associated with a high incidence of serious side effects and should be used with caution. It should be used with bimonthly follow-up of transaminases and blood cell counts; it should be restricted to cases intractable by other compounds; and it should be given for no longer than 2 months in case there is no clear response.

Topiramate significantly reduces the frequency of drop attacks, but in 1 trial, drop attacks persisted daily in most patients. In addition, the cognitive side effects of the drug may cause serious concerns (Glauser 1998). Thus, the future place of this compound in the treatment of Lennox-Gastaut syndrome still needs to be evaluated. One major issue relates to diagnostic criteria for patient inclusion. Topiramate was considered effective in a double blind study dedicated to Lennox-Gastaut syndrome (Glauser et al 2000), whereas comparing the effect in various syndromes, it appeared that the compound was much more effective in myoclonic-astatic epilepsy and Dravet syndrome than in KGS (Mikaeloff et al 2003).

Other drugs that have been effective in uncontrolled trials include nitrazepam (Chamberlain 1996). Vigabatrin has yielded variable results (Feucht and Brantner-Inthaler 1994). In 1 case report, seizures were made worse by gabapentin (Vossler 1996). Corticosteroid treatment with gradually tapered dosages may be helpful in idiopathic cases at onset, in status epilepticus, or during periods of worsening in the course of evolution (Roger et al 1989). Clinical trials of intravenous immunoglobulin have yielded equivocal results (Illum et al 1990; van Engelen et al 1994). Ketogenic diet, amantadine, tryptophane, flumazenil, imipramine, and many other treatments have had limited success in some patients (Dulac and N'Guyen 1993).

Although promising, vagal nerve stimulation still awaits further research (Lundgren et al 1998; Frost et al 2001). Although there was some claim based on review of the literature that vagal nerve stimulation and callosotomy give similar results, this was absolutely not the case in our hands. Vagal nerve stimulation was ineffective in the 10 patients with prior West syndrome who were submitted to this procedure, whereas 85% of the patients who underwent total callosotomy experienced dramatic improvement of their drop attacks (Pinard et al 1999).

Corpus callosotomy can reduce or abolish drop attacks in many patients with Lennox-Gastaut syndrome provided there is no major diffuse brain malformation, but it influences the pattern of other seizure types only rarely (Gates et al 1993). With the advent of new microsurgical techniques and the realization that anterior two-thirds section is sufficient in patients who started in school age, and adverse side effects of corpus callosotomy have been minimized. The choice of total versus anterior callosotomy depends, therefore, on the age at which the epilepsy started. Early onset in the first year of life indicates a probable involvement of parieto-occipital areas. Therefore, although slow spike-waves predominate in the frontal areas, posterior areas are still involved and would reappear following anterior cllosottomy (Pinard et al 1999).

Pregnancy
Although no information is available that is specific to this syndrome and pregnancy, information is available on epilepsy and pregnancy.

Anesthesia
No information is available.

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Abbreviations
EEG:electroencephalogram
EMG:electromyography
MRI:magnetic resonance imaging

ICD-9 Code
345.0

Synonyms
Akinetic epilepsy
Akinetic petit mal
Childhood epileptic encephalopathy with diffuse slow spike-and-waves
Lennox syndrome
Minor motor epilepsy
Mixed seizure disorder
Petit mal variant
Propulsive petit mal
Severe myokinetic epilepsy of early childhood with slow spike-and-waves

Subtopics
Cryptogenic Lennox-Gastaut syndrome
Secondary generalized epilepsy
Symptomatic generalized epilepsy
Symptomatic Lennox-Gastaut syndrome

Associated Disorders
Anoxic encephalopathy
Brain malformations
Central nervous system infection
Degenerative or metabolic disorders of the nervous system
Encephalopathy with multifocal epilepsy
Head injury
Porencephaly
Stroke
Tuberous sclerosis
West syndrome

Major Keyword Descriptors
ABO blood group incompatibility
absence seizures
aggressiveness
astatic seizures
atonic seizures
atypical absence seizures
autism
automatic behavior
cerebellar signs
clonic seizures
corpus callosotomy
cortical dysplasias
corticosteroids
drop attacks
felbamate
generalized tonic-clonic seizures
head nodding
hyperactivity
hypoglycemia
intellectual deterioration
intravenous immunoglobulin
lamotrigine
multiple seizure types
myoclonic seizures
myoclonus
personality changes
prematurity
prolonged labor
psychosis
rhizomelic seizures
sleep
slow spike-and-wave
tonic seizures
valproate

Minor Keyword Descriptors
epilepsy
mental retardation

Age of presentation
02-05 years
06-12 years

Age of Typical Presentation
02-05 years

Population Group(s) Preferentially Affected
none selectively affected

Occupation Group(s) Preferentially Affected
none selectively affected

Sex
male>female, >2:1

Family History
none

Heredity
none

Glossary
Lennox-Gastaut syndrome: A childhood-onset epileptic syndrome characterized by the clinical triad of diffuse slow spike-and-waves on EEG, mental retardation, and multiple seizure types in the same patient, including atypical absences and tonic and atonic seizures.

Permuted Topic, Synonyms, Subtopics
Lennox-Gastaut syndrome
Gastaut syndrome, Lennox-
epileptic encephalopathy with diffuse slow spike-and-waves, Childhood
encephalopathy with diffuse slow spike-and-waves, Childhood epileptic
diffuse slow spike-and-waves, Childhood epileptic encephalopathy with
slow spike-and-waves, Childhood epileptic encephalopathy with diffuse
spike-and-waves, Childhood epileptic encephalopathy with diffuse slow
myokinetic epilepsy of early childhood with slow spike-and-waves, Severe
epilepsy of early childhood with slow spike-and-waves, Severe myokinetic
motor epilepsy, Minor
generalized epilepsy, Minor
generalized epilepsy, Secondary
petit mal, Akinetic
petit mal, Propulsive
seizure disorder, Mixed
generalized epilepsy, Symptomatic
Lennox-Gastaut syndrome, Cryptogenic
Lennox-Gastaut syndrome, Symptomatic

Related Topics
Epilepsy
Epilepsy with continuous spike-and-waves during slow wave sleep
Sleep disorders associated with epilepsy

Differential Diagnosis
antiepileptic medication overdose
partial seizures secondary to structural lesions
posttraumatic epilepsies
encephalopathy with multifocal epilepsy
epilepsy with myoclonic-astatic seizures
epilepsy with myoclonic absences
continuous spike waves in slow sleep
late onset infantile spasms

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