Lennox-Gastaut Syndrome

Pierre Genton

Charlotte Dravet

Introduction

Among childhood epilepsies, Lennox-Gastaut syndrome (LGS) is one of the most severe. It is characterized clinically by frequent seizures, including sudden falls, marked resistance to therapy, and progressive mental and behavioral disturbances. The syndrome is difficult to treat, even with the most recent antiepileptic drugs. Although the physiologic and pathogenic mechanisms of LGS are not fully understood, it has precise, well-defined clinical and neurophysiologic characteristics that restrict the diagnosis to a fairly homogenous, albeit rather uncommon entity. Historically, its main trait (i.e., the presence of diffuse slow spike-wave discharges), has led to overdiagnoses and confusion with other encephalopathic epilepsies; not all diffuse slow spikes-and-waves, not all epileptic drop attacks, and not all severe, polymorphic encephalopathic childhood-onset epilepsies are caused by LGS. Indeed, some cases previously diagnosed as LGS would nowadays be reclassified into other categories, like myoclonic astatic epilepsy or the Dravet syndrome.

LGS has many possible causes, and modern concepts have stressed the major part played in the genesis of LGS by secondary bilateral synchrony originating from the frontal cortex. In spite of its relative rarity, LGS has in recent years been the object of specific clinical trials evaluating the efficacy of newer antiepileptic agents, probably because it still represents the archetype of a recognizable, yet severe, intractable childhood epileptic encephalopathy.

Historical Perspective

Early authors had already noticed the poor prognosis of some types of childhood seizures (i.e., atypical absences, tonic seizures, and astatic seizures), when Gibbs in 1938³⁸ and then Gibbs et al.³⁹ in 1939 identified an electroencephalographic (EEG) pattern characterized by slow (about 2-Hz) spikes-and-waves. They called this the petit mal variant as opposed to the less severe petit mal absence, characterized by 3-Hz spikes-and-waves. Lennox in 1945⁵⁷ and Lennox and Davis in 1950⁵⁹ established the clinical correlates of this pattern and described a symptomatic triad comprising slow diffuse spikes-and-waves, mental deficiency, and three seizure types: Myoclonic jerks, atypical absences, and head drops or falls, the latter successively described as akinetic seizures, astatic seizures, and finally drop attacks.

The further studies by Sorel⁸⁰ and Doose et al.,²⁵ and the MD dissertation of Dravet, published by Gastaut et al.,³³ allowed precise characterization of the electroclinical features of the syndrome. Different denominations were used over the years (including such complex ones as childhood epileptic encephalopathy with diffuse slow spike-waves) until the consensual denomination of Lennox-Gastaut syndrome was proposed by Margaret Buchtal-Lennox in 1966, in tribute to both the initial work of Lennox⁵⁷^,⁵⁸ and the thorough clinical description performed by the Marseille school. Further investigations included the long-term studies of large series reported by Oller Daurella,⁶⁹ Gastaut et al.,³⁴ Loubier,⁶⁰ Ohtahara et al.,⁶⁸ Beaumanoir,¹¹ and Chevrie and Aicardi.¹⁸ Of particular interest from a clinical, genetic, and therapeutic perspective is the progressive delineation of LGS from other encephalopathic epilepsies like myoclonic astatic epilepsy (the Doose syndrome), severe myoclonic epilepsy of infancy (the Dravet syndrome), the syndrome of continuous spikes-and-waves during slow-wave sleep, and specific encephalopathies like the Angelman syndrome.

Definitions

In the International Classification of Epilepsies and Epileptic Syndromes,²⁰ LGS is classified among the symptomatic or cryptogenic generalized epilepsies. It is defined by several criteria:

Onset during childhood
Coexistence of several seizure types, with mainly atypical absence, axial tonic, and atonic seizures; the presence of tonic seizures during sleep is a constant feature; other seizures (myoclonic, generalized tonic–clonic, focal) can occur
Diffuse slow spikes-and-waves and bursts of fast rhythms at 10 to 12 Hz during sleep
Permanent psychologic disturbances with psychomotor delay, personality disorders, or both

The seizure frequency is high, and episodes of status are not uncommon. In the EEG, focal and multifocal abnormalities can be associated with the diffuse slow spikes-and-waves. These electroclinical features may occur in a previously normal child, without pathologic antecedents and without signs of brain lesion, usually between the ages of 1 and 8 years, and constitute the cryptogenic form of LGS. They also can occur in a child with prior signs of brain damage, sometimes in the wake of another type of epilepsy, such as infantile spasms or focal epilepsy, and constitute the symptomatic forms of LGS. In the latter cases, the range of ages at onset may be wider (between 1 and 15 years, rarely more).

In the 2001 proposal of the ILAE,²⁹ LGS was classified among epileptic encephalopathies, a category of epilepsies in which the epileptiform abnormalities may contribute to progressive dysfunction.

Epidemiology

Epidemiologic data on LGS vary greatly. Different criteria were used in selecting cases. Some studies have included all forms of severe childhood epilepsies associated with slow spikes-and-waves on the EEG. Others have restricted the criteria to those defined above. Its frequency has thus been estimated to range
from 3% to 10.7% of all cases of childhood epilepsies.⁴^,¹¹^,³⁴ In the population observed in the Centre St. Paul, which specializes in the treatment of severe epilepsies, the figure is 3.7% in the whole population (children and adults) and 6.6% in patients with onset before age 10 (personal data from a prospective registry of all newly referred epilepsy cases seen between 1986 and 1996). A study performed in metropolitan Atlanta, GA, found a prevalence of 4% among children aged <10.⁸⁴ Another study performed in Finland found a yearly incidence of 2 per 100,000 of “broadly defined” LGS among children aged 1 to 14 years.⁴⁷

There is no particular geographic or ethnic distribution. Boys are slightly more often affected than girls.⁶⁰^,⁶¹^,⁶⁸ A closer look at patient registries would probably show that the incidence has declined in recent years, due to stricter diagnostic criteria, leading to other specific diagnoses and to changes in the early treatment of severe childhood epilepsies that may have avoided the progression of symptomatic cases into the full-blown LGS. In our recent experience, the incidence of LGS has been comparable to that of myoclonic astatic epilepsy and the Dravet syndrome.

Etiology and Basic Mechanisms

LGS can be symptomatic or cryptogenic. Numerous etiologies can be found in the symptomatic forms¹²: Perinatal anoxic ischemia; antenatal or perinatal vascular accident; antenatal, perinatal, or postnatal cerebral and cerebromeningeal infection; HHE (hemiconvulsion-hemiplegia-epilepsy) syndrome; both diffuse and lateralized or even focal brain malformation and migration disorders; tuberous sclerosis, Down syndrome, hydrocephalus, head trauma, brain tumor and radiotherapy for brain tumor, and many others. There are numerous publications on uncommon etiologies, and a sample may be quoted here to underline the etiologic heterogeneity of this syndrome. LGS may, for instance, occur following chemo- and whole-brain radiotherapy for acute lymphocytic leukemia⁶³; in an encephalitic form of neurocysticercosis¹; or in common variable immunodeficiency with acute disseminated encephalomyelitis.⁵³

In some cases, despite psychomotor retardation before the onset of seizures or of mild to moderate, nonspecific cerebral atrophy demonstrated by computed tomography (CT) and magnetic resonance imaging (MRI), there is no recognizable etiology. When epilepsy starts in the first year of life, it is often in the form of infantile spasms, followed by LGS. Otherwise, LGS can be preceded by focal seizures, or all the features of LGS may be manifesting at onset or soon thereafter. It must also be stressed that the typical features of LGS can be observed only transiently in some patients.¹¹ In the cryptogenic forms, there is no etiology by definition. However, “cryptogenicity” may depend on the amount of investigation, and this category may have shrunk since the availability of MRI. Some authors have been enticed to subdivide LGS patients in three categories: Symptomatic, noncryptogenic, and cryptogenic, the latter category referring to individuals with strict criteria of normal development, lack of dysmorphism, and normal MRI⁴¹: Using such criteria, these authors found no difference in seizure outcome between these etiologic categories.

The mechanisms underlying LGS are not well understood. In 1987, Theodore et al.⁸² used positron emission tomography (PET) to investigate the cerebral metabolism of ten patients, and Chugani et al.¹⁹ that of five, without considering the various etiologies. Their results appear too heterogeneous to be significant. Microscopic studies of samples obtained at autopsy and brain biopsy from 15 patients were reported by Roger and Gambarelli-Dubois.⁷⁵ Selective neuronal necrosis was observed in the neocortex, hippocampus, thalamus, and cerebellum, but in eight cases the necrosis was restricted to the cerebellum. Electron microscopic examination of biopsy material from eight patients showed that neuronal loss occurred mainly at postsynaptic sites. Quantitative analysis confirmed the rarefaction of cortical dendrites and synaptic contacts. In two cases studied by Renier,⁷³ there were a few swollen astrocytes around the neurons in the deeper cortical layers, poor dendritic arborization, and disturbed synaptic development of the pyramidal cells restricted to the inner cortical layers. He hypothesized that these findings were the origin and not the consequence of LGS, and were perhaps related to an autoimmune process. A virologic and immunologic approach was adopted by Smeraldi et al.,⁷⁹ but the results of their studies were not significant. Eeg-Olofsson²⁸ discussed the relationships between a genetic defective immune mechanism and the occurrence of LGS.

Genetic factors do not seem to play a major part in LGS, and no multiplex families with LGS have been reported. The frequency of cases with a family history of epilepsy ranges from 2.5%¹⁸ to 28%.⁶⁰ Boniver et al.¹⁶ noted that 48% of patients with cryptogenic LGS had a family history of either epilepsy or febrile convulsions, but their series may have included patients with myoclonic astatic epilepsy. Interestingly, no case of LGS has been reported in large generalized epilepsy with febrile seizures plus (GEFS+) families, which include patients with Dravet syndrome or myoclonic astatic epilepsy. Among genetically determined cortical brain malformations, LGS may occur in patients with micropolygyria and in those with the XLIS mutation, which causes subcortical band heterotopia in females and pachygyria in males. In the latter example, the occurrence of LGS seems to be correlated with the thickness of the band or severity of pachygyria.⁴²

The neurophysiologic processes leading to the production of interictal EEG changes and seizures in LGS have received some attention. Processes related to those occurring in idiopathic generalized epilepsies play a limited part, since abnormal sleep patterns found in patients with cryptogenic LGS seem to originate outside the usual thalamocortical circuit.⁸⁸ Secondary bilateral synchrony (SBS), which is of cortical origin, appears to be at the origin of the apparently generalized EEG changes: In their study comparing myoclonic seizures found in LGS and in (truly idiopathic) myoclonic astatic epilepsy, Bonnani et al.¹⁵ convincingly demonstrated propagation from a lateralized origin in LGS. There is no satisfactory explanation for the genesis of this abnormal tendency to SBS and related inhibition of function, but this phenomenon clearly plays a major part in the genesis of both seizures and cognitive impairment. The occurrence of the LGS at a crucial stage of neurodevelopment is of course a major factor of the learning difficulties and progressive retardation, and Blume¹⁴ has hypothesized that the intensity of interictal and ictal discharges diverts the brain from normal developmental processes toward seizure control mechanisms.

In the light of recent data, LGS appears to be an acquired, nonspecific, age-dependent diffuse encephalopathy, occurring without specific familial predisposition, and the reason why it appears in either normal or brain-damaged patients is not known.¹² There is evidence of major focal factors, related to the frontal lobes, but these coexist with a predisposition to bilateral synchrony, which accounts for most of the clinical features. Until we know more, this epileptic encephalopathy should thus still be ranked among the “generalized” syndromes.

Clinical Presentation

The onset is before the age of 8, with a peak between 3 and 5 years. Onset after age 10 is unusual. In cryptogenic cases,¹⁶ the first seizures can be myoclonic, atypical absences, or falls, sometimes repeated in status. Sometimes, an isolated
seizure—tonic, clonic, tonic–clonic, or even a unilateral seizure—has preceded the typical seizures by several months. Nocturnal tonic attacks are usually not observed at the very onset. Psychological and cognitive disturbances can be concomitant with the first seizures or can develop later, insidiously. Thus, it is not easy to make the diagnosis of LGS very quickly. The EEG features at onset can consist of either diffuse slow spikes-and-waves or only more or less diffuse slow waves. A single case study of nocturnal sleep at this stage has been published,²¹ demonstrating the presence of bursts of low-voltage rapid rhythms evoking subclinical tonic seizures. When LGS follows infantile spasms, there are two possible modalities: Either infantile spasms are replaced by tonic seizures without a free interval, or infantile spasms disappear and both the EEG and the psychomotor development improve for some time before falls, atypical absences, and diffuse slow spikes-and-waves appear, accompanied by a new slowing of development. When LGS complicates other types of epilepsy, the diagnosis is marked by the onset of falls and behavioral/cognitive changes. Several authors have reported the occurrence of LGS in adolescents and young adults who previously had an idiopathic type of generalized epilepsy.⁵⁹^,⁶⁸^,⁷⁴

Interictal Symptomatology

The neuropsychological and psychiatric symptoms consist of arrest or slowing of psychomotor development, apparent deterioration of cognitive abilities, and appearance of psychiatric conditions, the expression of which depends on age. The youngest children are seen with physical and intellectual instability, mood lability, inability to acquire new skills, and progressive disharmony. Older children exhibit slowness of ideation and expression; language deterioration resulting from motor dysfunction, particularly changes in muscular tone of the orolaryngopharyngeal area¹⁰; aggression; irritability; loss of social relationships; tendency to isolation; and sometimes psychotic outcome. Personality disorders are always present in the cryptogenic forms.⁸⁹ There are no neurologic signs that can be considered specific to LGS, apart from transient cerebellar, pyramidal, or extrapyramidal signs during prolonged status. However, in some patients the recurrent episodes of status are so long and so frequent that this semiology can become permanent after more than 10 years of evolution. Iatrogenic factors may contribute to neurologic deterioration.

On the EEG, the background can be disorganized, with diffuse slow waves, poor reactivity, and lack of topographic differentiation. Such disorganization can be permanent (67% of patients) or transient, appearing only during periods of worsening of seizures. Constant disorganization is a sign of poor prognosis. Hyperventilation can elicit slow spike-and-wave discharges with or without clinical correlates (atypical absences), whereas intermittent photic stimulation has no effect. Paroxysmal changes are frequent, with discharges of diffuse slow spikes-and-waves and slow polyspikes-and-waves. In 75% of children, they are associated with focal and multifocal changes (spikes, slow spikes, slow spikes-and-waves), with constant or variable focalization, frequently frontal or temporal. They are increased during slow sleep, when the diffuse slow spikes-and-waves become more synchronous and rhythmic, with prominent polyspikes. During sleep, specific bursts of fast rhythms appear (see below). The differentiation of sleep stages can be preserved or can be blurred⁷ (Fig. 1).

Ictal Symptomatology

In order of decreasing specificity, LGS, a disorder associated with multiple seizure types, includes tonic seizures, atypical absences, atonic seizures, and other types. Both tonic and atonic seizures may cause falls.

Tonic seizures are the main feature of the syndrome and are reported in 74%¹¹^,³⁴ to 90%⁶⁰ of patients. They can be axial, axorhizomelic, or complete, and symmetric or markedly unilateral. They can occur while patients are awake or asleep. The neck and body are suddenly flexed, the shoulders and arms are raised in a semiflexed or extended position, the legs are extended, the facial muscles (sometimes only of the lower lip) contract, and the eyes roll up. Apnea and facial flushing are apparent. The victim may fall suddenly. Loss of consciousness does not always occur and is rarely the initial symptom. Return to normal consciousness always coincides with the end of the EEG discharge. Enuresis can occur. The pupils are usually dilated. When these seizures are short and involve only rolling of the eyes and respiratory changes (which is usually the case during sleep), they may remain unnoticed. When they last for more than 10 seconds, they can culminate in a tremor that affects the whole body (resulting in a “vibratory” seizure). In tonic–automatic seizures, described by Oller Daurella⁷⁰ in 72% of late-onset cases, there is a final phase of gestural, sometimes ambulatory automatisms. Slow-wave sleep facilitates the occurrence of tonic seizures. The EEG during tonic seizures (Fig. 2) consists of either a bilateral discharge of fast rhythms, predominantly in the anterior areas and at the vertex, or a flattening of the background, or a combination of these two patterns, sometimes preceded by generalized spikes-and-waves, followed by diffuse slow waves and slow spikes-and-waves, that last longer in patients with “tonic–automatic” seizures. There is no postictal silence. The fast discharges are particularly common during slow-wave sleep, when they can be nearly subclinical. Gibbs³⁸ inappropriately described this ictal pattern recorded during sleep as the grand mal pattern.

Atypical absences are observed in a vast majority of patients. Clinically, they are often difficult to diagnose: The onset and end are gradual, contact is impaired but not completely lost, a simple activity can be continued, eyelid myoclonus is not rhythmic, perioral myoclonus is frequent, and slow forward motion of the head caused by loss of tone, as well as drooling, is also frequent. In the EEG, atypical absences are associated with often irregular, more or less symmetric discharge of diffuse slow spikes-and-waves at 2 to 2.5 Hz (Fig. 3), or with a burst of rapid rhythms, or with a mixed pattern.

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