Epilepsia, 52(Suppl. 5):39, 2011 doi: 10.1111/j.1528-1167.2011.03177.

LENNOX-GASTAUT: CARE FOR A LIFETIME

Denition and natural history of Lennox-Gastaut syndrome

Peter R. Cameld
Division of Neurology, Department of Pediatrics, Dalhousie University and the IWK Health Centre, Halifax, Nova Scotia, Canada

SUMMARY
Lennox-Gastaut syndrome (LGS) is a rare epileptic encephalopathy with a peak age of onset of 35 years of age. Reported prevalence rates for LGS vary widely from 110% of all childhood epilepsies. Incidence rates are much lower. LGS is characterized by intractable, multiple, generalized seizure types and an interictal electroencephalogram showing bursts of slow spike-and-wave, paroxysmal bursts of generalized polyspikes, and a slow background. All patients have tonic seizures during sleep that may be subtle, and nearly

all have treatment-resistant, lifelong epilepsy. Cognitive stagnation and behavioral problems are seen in almost all patients and lead to a life of dependency. The differential diagnosis includes other symptomatic generalized epilepsies and pseudo-Lennox syndrome. Misdiagnosis is common. Children and adults with LGS have an enormous impact on their families, and efforts to improve the quality of life for these patients are complex. KEY WORDS: Atypical absence seizures, Differential diagnosis, Epilepsy, Lennox-Gastaut syndrome, Tonic seizures.

A large body of literature has been published about Lennox-Gastaut syndrome (LGS), which includes several recent comprehensive and thoughtful reviews (Dulac & NGuyen, 1993; Arzimanoglou et al., 2009; Hancock & Cross, 2009). LGS was described in 1966 by the Marseille School in France, where Gastaut et al. (1966) generously proposed the term Lennox syndrome to denote a childhood-onset epilepsy characterized by frequent tonic and absence seizures. The definition of LGS subsequently was clarified by the International League Against Epilepsy (ILAE) in 1989 (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). The most common seizures included were tonic and atypical absence, followed by myoclonic, tonic/atonic drops, generalized tonicclonic, and focal seizures (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). The seizures are thought to be typically intractable. Cognitive impairment is nearly universal, and electroencephalography (EEG) shows a slow (2.5 Hz) spike-and-wave pattern (Commission on Classification and Terminology
Address correspondence to Peter R. Camfield, M.D., IWK Health Centre, 5850/5980 University Ave, PO Box 9700, Halifax, NS B3K 6R8, Canada. E-mail: camfield@Dal.Ca Wiley Periodicals, Inc. 2011 International League Against Epilepsy

of the International League Against Epilepsy, 1989). This classic triad continues to be diagnostic; however, it must be emphasized that not all patients have all of the core seizure types, especially at onset (Arzimanoglou et al., 2009). In addition, most experts now agree that tonic seizures during sleep are required for the diagnosis. The tonic seizures associated with LGS may be subtle and are associated with generalized, approximately 10- to 15-Hz, lowvoltage spike discharges on EEG. LGS is considered an epileptic encephalopathy, a concept formally endorsed in 2006 by ILAE and further emphasized in 2010 (Berg et al., 2010). The term implies that the epileptic activity, both the seizures themselves and the EEG spike discharges, contribute to mental deterioration/stagnation and behavioral disorders. Some other age-specific epileptic encephalopathies include Dravet syndrome (Dravet et al., 2005), Ohtahara syndrome (Yamatogi & Ohtahara, 2002), and West syndrome (Osborne et al., 2010). Onset of LGS usually occurs before age 8, with a peak between 3 and 5 years of age (Arzimanoglou et al., 2009; Hancock & Cross, 2009). LGS has been estimated to account for 110% of childhood epilepsies; however, this very wide range is likely the result of loose diagnostic criteria with a tendency to label all patients with mixed types of generalized seizures and intellectual disability as 3

4 P. R. Cameld having LGS (Trevathan et al., 1997; Hancock & Cross, 2009). A more systematic study of children in Atlanta, Georgia, found an epilepsy prevalence of 6 per 1,000 children, with 4% classified as LGS (Trevathan et al., 1997). Because LGS rarely remits, prevalence studies should find a higher frequency of LGS than incidence studies. This is well illustrated by the Nova Scotia population-based study of children with new-onset epilepsy (incidence cases). In that study, 12% had symptomatic generalized epilepsies (SGEs); however, only 4% of those with SGE had LGS (Camfield et al., 1996). Of all new-onset epilepsies, the incidence of LGS was only 0.6%. Given that the diagnostic clinical and EEG features may not be present at epilepsy onset, the diagnosis of LGS may emerge only over several years. In the Nova Scotia cohort, there were only four patients with LGS at the time of epilepsy diagnosis; however, 20 years later the number had increased to 17, with most of the new cases evolved from West syndrome (Camfield & Camfield, 2007). Camfield & Camfield, 2008; Arzimanoglou et al., 2009; Hancock & Cross, 2009). Cognitive impairments are clinically apparent in an estimated 2060% of patients at the time of diagnosis of LGS (Arzimanoglou et al., 2009). The cognitive impairment usually becomes more apparent over time, and within 5 years of onset, serious intellectual problems have been noted in 7595% of patients (Beaumanoir & Blume, 2005; Hancock & Cross, 2009). It is not always clear if LGS is associated with actual cognitive deterioration or simply stagnationprogressive brain deterioration or damage versus failure of brain development. Cognitive skills may fluctuate according to seizure frequency (Dulac & NGuyen, 1993), suggesting the problem is one of interference in normal development rather than destruction of brain tissue. IQ represents a ratio with intellectual function as the numerator and chronologic age as the denominator. IQ drops if intellectual function remains stable (stable numerator) as the child ages (increasing denominator). I am unaware of published psychological assessments in LGS over time that have reported absolute values for intellectual function rather than IQ, so the issue of deterioration versus stagnation has not been resolved. It has been suggested that favorable cognitive outcomes are more likely in patients with a later age of LGS onset. In a retrospective chart review from the Mayo Clinic (referred patients), 74 of 107 patients with LGS were followed for 3 years (Goldsmith et al., 2000). Overall, 8% had a favorable cognitive outcome that was defined as normal or borderline intelligence based on clinical impression only (no formal psychological testing). The six patients with favorable cognitive outcome were 9.5 (median) years of age at onset. Patients who were judged initially to have normal cognitive function but mental handicap at follow-up had a median age of LGS onset of 4.5 years. Gastaut and colleagues had come to a similar conclusion many years earlier (Arzimanoglou et al., 2009). Along with cognitive problems, many patients with LGS develop behavioral and psychiatric disorders (Glauser, 2004). It is uncertain if these problems differ in people with an intellectual disability alone; however, attentional problems, aggression, and autistic features can be very prominent in LGS and represent enormous challenges for the family. Seizure types Tonic and atypical absence seizures are the most prominent seizure types in LGS, although others may be troublesome, including nonconvulsive status epilepticus, myoclonia, and focal or generalized tonicclonic and atonic/akinetic seizures. (Dulac & NGuyen, 1993; Arzimanoglou et al., 2009).

Etiology
The etiology of LGS has been divided into two groups. Approximately 75% of cases are thought to be symptomatic, implying an identifiable cause such as a cerebral malformation or hypoxicischemic injury (Gastaut et al., 1966; Hancock & Cross, 2009; Borggraefe & Noachtar, 2010). Identifiable causes are usually the result of a static brain disorder; progressive metabolic disorders are extremely rare. The cryptogenic group (no apparent cause and no neurologic precedents) may account for approximately 25% of cases (Hancock & Cross, 2009). However, the attribution of cryptogenic is highly dependent on the sophistication of the investigations, and it has been argued that the use of this term should be dropped (Engel & International League Against Epilepsy, 2001). When LGS has no apparent cause, a genetic predisposition (Blume, 2001) or autoimmune (Goldsmith et al., 2000) influence has been hypothesized, but without strong evidence. Blume has thoughtfully considered the mysteries of the etiology and pathophysiology of LGS (Blume, 2001). He pointed out that three factors continue to hamper our understanding: lack of an animal model, little progress in understanding the genetic contributions, and the multitude of etiologies. There is considerable evidence to implicate cortical hyperexcitability at a critical age of development; however, in my opinion, a consistent understanding of the pathogenesis of LGS remains elusive.

Clinical Characteristics of LGS

LGS has profound deleterious effects on intellectual and psychosocial function (Dulac & NGuyen, 1993;
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5 Denition and Natural History of LGS Tonic seizures Tonic seizures vary in severity but are the most important seizures associated with LGS. These seizures are required for the diagnosis (Arzimanoglou et al., 2009), although they may not always be present at onset of LGS. Tonic seizures may be subtle and limited to eye movements (especially brief tonic upgaze), alterations in respiration, or facial tightening with neck flexion and a brief vocalization. More dramatic tonic seizures may involve axial muscles only or nearly the entire body, sometimes with a vibratory component (tonic vibratory) (Dulac & NGuyen, 1993). The frequency of tonic seizures, especially if they are subtle, is easily underestimated because they occur most often during sleep [particularly nonrapid eye movement (REM) sleep]. The associated EEG shows a sudden onset of generalized, diffuse, rapid (1013 Hz), low-amplitude spikes that predominate in the vertex and anterior electrode positions and within the burst may increase progressively in amplitude and decrease in frequency (Dulac & NGuyen, 1993). The bursts may last a few seconds to several minutes but typically are 510 s in duration. Following the bursts, there usually is an abrupt return to background rhythms or a short epoch of generalized, high-amplitude delta; however, the EEG does not show generalized suppression that is more typical of other tonic seizures (Dulac & NGuyen, 1993). Atypical absence Atypical absence is the second most common seizure type in LGS. This seizure type is not defined easily, and because the seizures may be subtle, they are not easily recognized. As in typical absence, the main clinical manifestation is a brief lapse in consciousness, although some awareness may be preserved (Arzimanoglou et al., 2009). The onset and termination of atypical absence seizures are not always apparentpatients may seem to fade in and out of consciousness. The accompanying EEG shows slow and often irregular spike waves (2.5 Hz) that may be difficult to distinguish from interictal bursts (Dulac & NGuyen, 1993). Sudden tonic or atonic falls (drop attacks) At least 50% of patients with LGS have drop attacks. Unlike tonic and atypical absence seizures, there is nothing subtle about drop attacks. They often are preceded by a single generalized myoclonic jerk followed by a tonic contraction of axial muscles or axial atony or a combination that leads to a sudden fall. The falls are so sudden that even a vigilant caretaker cannot prevent injury; hence, drop attacks represent a nightmare for the family. In the authors experience, the only way to prevent facial injuries is for the patient to wear a helmet with a full face mask, which is highly stigmatizing and often impractical, for example, eating is difficult. Drop attacks are not diagnostic for LGS, as they are seen in other epilepsy syndromes, particularly myoclonicastatic epilepsy (Camfield & Camfield, 2002; Arzimanoglou et al., 2009). Nonconvulsive status epilepticus Nonconvulsive status epilepticus is thought to occur in about two thirds of LGS patients (Hancock & Cross, 2009) and consists of continuous or nearly continuous atypical absences that cause varying levels of diminished consciousness. Nonconvulsive status may also feature occasional superimposed brief tonic seizures (Dulac & NGuyen, 1993). Not surprisingly, the simultaneous EEG shows a nearly continuous slow spike-and-wave pattern occasionally interrupted by brief bursts of generalized polyspikes (Dulac & NGuyen, 1993). Nonconvulsive status may last from hours to weeks and is particularly difficult to recognize in patients with severe cognitive impairment. It is not easy to assess the effect of these prolonged episodes; however, there is a strong suspicion that nonconvulsive status is a major contributor to intellectual impairment. Myoclonic seizures Most patients with LGS have myoclonic seizures that may be subtle or severe enough to cause falls. Myoclonia are not required for the diagnosis of LGS and occur in many other epilepsy syndromes (Camfield & Camfield, 2002; Arzimanoglou et al., 2009). Other seizure types Other seizure types that may occur in LGS include generalized tonicclonic, unilateral clonic, and focal clonic with or without secondary generalization. These seizures seem to occur most frequently in the later stages of LGS. However, the diagnosis of LGS may be obscured if they are very frequent (Arzimanoglou et al., 2009).

EEG Features of LGS

The hallmark EEG feature in LGS is slow (2.5 Hz) spike-and-wave bursts with abnormal background activity (Fig. 1) (Commission on Classification and Terminology of the International League Against Epilepsy, 1989; Zupanc, 2009). The spikes tend to be broad and approach 70200 ms and are followed by a positive deep trough and a surface negative wave (350400 ms) (Dulac & NGuyen, 1993; Arzimanoglou et al., 2009; Hancock & Cross, 2009). Not every wave is preceded by a spike, and the bursts may be remarkably irregular without a clear onset and offset. Bursts may come and go over long periods of time. The distinction between ictal and interictal discharges may be impossible, particularly in patients with significant cognitive impairment; however, clinically apparent atypical absence seizures always have an associated slow spike-wave burst. It is unclear why the slow spike-wave bursts in LGS differ from the more
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6 P. R. Cameld

Figure 1. EEG in Lennox-Gastaut: slow and irregular spike and wave discharge. From Zupanc (2009). Copyright 2009 by John Wiley and Sons. Reprinted by permission of SAGE Publications. Epilepsia ILAE

Figure 2. EEG in Lennox-Gastaut: a tonic seizure during sleep. From Zupanc (2009). Copyright 2009 by John Wiley and Sons. Reprinted by permission of SAGE Publications. Epilepsia ILAE

typical 3-Hz spike-wave discharges, which nearly always have clinical manifestations if they last longer than 34 s (Arzimanoglou et al., 2009). Bursts of generalized fast polyspikes (1020 Hz), especially during sleep, also define the EEG profile of the LGS (Fig. 2) (Donat, 1992; Dulac & NGuyen, 1993; Blume, 2001; Arzimanoglou et al., 2009; Hancock & Cross, 2009; Zupanc, 2009). Many, but not all, of these bursts are associated with clinically apparent tonic seizures or absence with tonic features (Blume, 2001), although the clinical features may be subtle. The EEG background probably is never normal in LGS and shows a diffuse increase in theta and delta with slow dominant rhythms.

Differential Diagnosis of LGS

Many other epileptic syndromes fulfill one or more criteria of LGS and include focal epilepsies with secondary bilateral synchrony, myoclonicastatic epilepsy (Doose syndrome), atypical benign focal epilepsy of childhood
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(Aicardi & Chevrie, 1982; Hahn, 2000), Dravet syndrome, and West syndrome (Oguni, 2010). Tonic seizures are not exclusive to LGS and are seen prominently in West syndrome and some focal epilepsies, especially those with frontal lobe onset (Dulac & NGuyen, 1993). Drop attacks, which are seen frequently in LGS patients, occur in many other syndromes. The diagnosis of LGS often is incorrect (Dulac & NGuyen, 1993); one study reported misdiagnosis in 38 of 103 patients who were referred with a diagnosis of LGS (Beaumanoir, 1982). The classification of epileptic syndromes remains controversial. Worldwide the most commonly used scheme continues to be the 1989 version from the ILAE (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). That scheme recognizes SGE as a major category and within this category notes seven specific syndromes: West syndrome, LGS, myoclonicastatic epilepsy, epilepsy with myoclonic absences, early myoclonic encephalopathy, early infantile encephalopathy, and Ohtahara syndrome. Four other syndromes are mentioned that may or may not be

7 Denition and Natural History of LGS generalized: neonatal seizures, severe myoclonic epilepsy of infancy, continuous spike wave in slow sleep, and Landau-Kleffner syndrome. The concept of SGE specifies a generalized brain abnormality that is associated with generalized seizure(s) types. Many patients with symptomatic generalized epilepsy with multiple seizure types plus an intellectual disability cannot be assigned to a specific epilepsy syndrome (Camfield & Camfield, 2007). It is our impression they often are loosely diagnosed to have LGS; however, they do not meet the usual criteria and assigning this label is of little clinical benefit (Dulac & NGuyen, 1993; Camfield & Camfield, 2007). The diagnosis of LGS must be based on a detailed history andat a minimumawake and sleep EEGs. An overnight video-EEG may be revealing, although no study has formally compared the diagnostic yield of a routine sleep EEG with video and an overnight video-EEG study for detection of tonic seizures in LGS. Because LGS may evolve from other syndromes, particularly West syndrome, the diagnosis may emerge only after several years of follow-up. West syndrome A Cochrane review suggested that about 20% of LGS cases are preceded by West syndrome (Hancock & Cross, 2009). In the population-based, 20-year follow-up study of 692 children with epilepsy in Nova Scotia, West syndrome evolved into LGS in one third of the children with West syndrome, and 65% of those with LGS had earlier West syndrome (Camfield & Camfield, 2007). Another clinic-based study designed to investigate the etiology of LGS found that 24 of 72 LGS cases (33%) evolved from West syndrome (Oguni, 2010). Weinmann also noted that 17.8% of 174 children with Lennox-Gastaut syndrome had preceding West syndrome (Weinmann, 1988). Another connection between West syndrome and LGS is the observation that anoxic episodes in early life have been identified in approximately 40% of patients who develop LGS from West syndrome (Blume, 2001). West syndrome is defined by infantile spasms plus hypsarrhythmia on EEG. The age of onset typically is before 1 year of age (peak 47 months), which is much younger than age of onset in LGS (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). Later onset of West syndrome is uncommon, but when it does occur, video-EEG recording of a cluster of spasms may be necessary to distinguish it from LGS (Dulac & NGuyen, 1993). LGS patients with a history of West syndrome almost always have a poor epilepsy and intellectual prognosis (Dulac & NGuyen, 1993). Ohtahara syndrome Ohtahara syndrome is a rare early infantile epileptic encephalopathy. Prior to its description in 1976, Ohtahara syndrome was classified as neonatal West syndrome (Commission on Classification and Terminology of the International League Against Epilepsy, 1989; Donat, 1992; Ohtahara, 2007). Patients with Ohtahara syndrome have frequent brief tonic spasms that usually begin in the first month of life, although a few patients also have myoclonic or even focal seizures (Donat, 1992). All have severe neurologic impairment with devastating mental handicap. The interictal EEG shows a burst-suppression pattern with 15 s bursts of high amplitude mixed frequencies with multifocal spikes and sharp waves. The suppression periods last 310 s (Donat, 1992; Ohtahara, 2007). This pattern should be easily distinguishable from the less frequent and less periodic generalized polyspike bursts of LGS. At age 46 months, Ohtahara syndrome may evolve to West syndrome (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). In one study, 12 of 16 children with Ohtahara syndrome followed this sequence (Ohtahara, 2007). It has been suggested that the transition from Ohtahara syndrome to West syndrome and then to LGS indicates a common pathophysiology for these three childhood-onset epileptic encephalopathies (Ohtahara, 2007). Dravet syndrome Dravet syndrome is a well-recognized childhood epileptic encephalopathy that should not be difficult to distinguish from LGS (Dravet et al., 2005; Arzimanoglou, 2009). In the first year of life, a previously normal child develops prolonged focal seizures, usually with fever. In the second or third year, a mixture of other devastating seizures develops including myoclonus, atypical absence, short generalized tonicclonic seizures, and focal seizures. Drop attacks are uncommon, and tonic seizures during sleep are exceedingly rare. The interictal EEG initially is normal but eventually shows background slowing with brief bursts of irregular generalized spike waves that may be photosensitive, but usually not with a frequency of <2.5 Hz (Dravet et al., 2005; Arzimanoglou, 2009). All seizure types are resistant to pharmacologic treatment with antiepileptic drugs (AEDs). By the second year of life, cognitive impairment is apparent, coupled with behavioral disorders, especially severe hyperactivity. About 70% of patients with Dravet syndrome have severe, de novo, truncating or nonsense mutations in the SCN1A gene that defines the etiology (Dravet et al., 2005). Myoclonicastatic epilepsy (Doose syndrome) Myoclonicastatic epilepsy, or Doose syndrome, may be difficult to distinguish from LGS. The onset typically is between 1 and 5 years of age in an otherwise healthy, intellectually normal child who develops multiple generalized tonicclonic seizures and/or myoclonicastatic seizures (Commission on Classification and Terminology of the International League Against Epilepsy, 1989;
Epilepsia, 52(Suppl. 5):39, 2011 doi: 10.1111/j.1528-1167.2011.03177.x

8 P. R. Cameld Doose, 1992). Within a short time all develop myoclonic astatic seizures, which are required for the diagnosis. The classical myoclonicastatic seizure begins with a sudden myoclonic extension of both arms with neck flexion, followed by an axial tonic contraction that causes the child to fall. The falls are sudden and dramatic. There is a strong genetic component (likely polygenic) to this syndrome, and according to Professor Doose, the extent of genetic influences determines the clinical course and prognosis (Doose & Baier, 1987; Doose, 1992). EEG shows a normal background with paroxysmal 4-Hz theta bursts accompanied by generalized bursts of spike-waves and polyspike waves (Commission on Classification and Terminology of the International League Against Epilepsy, 1989; Doose, 1992). The prognosis is variable. In the majority of patients, myoclonicastatic epilepsy has a spontaneous and permanent remission within a few years of onset. In most patients, the seizures are quickly controlled with AEDs (particularly valproic acid) that can be withdrawn successfully after 12 years. In others, seizures vanish without AED treatment. In a small number of cases, myoclonicastatic epilepsy is severe and over time becomes indistinguishable from LGS (Doose, 1992; Camfield & Camfield, 2002). Pseudo-Lennox/atypical benign partial epilepsy This syndrome, also known as atypical benign partial epilepsy, is likely the same as LGS transient (Donat, 1992). EEG shows central spikes that are identical to those of benign focal epilepsy of childhood with centrotemporal spikes (benign rolandic epilepsy), but in addition, there are very frequent spike-wave complexes that are synchronous over the frontocentral areas. Seizures usually are predominantly drop attacks; however, focal seizures involving the face are typically present as well. Clusters of seizures are typical and there may be striking periods with few or no seizures (Arzimanoglou et al., 2009). The etiology of pseudo-Lennox syndrome is unclear. However, it has been suggested this syndrome may begin as benign rolandic epilepsy that is modified by medication toxicity or illness (Donat, 1992). Unlike LGS, in pseudo-Lennox syndrome the EEG does not show bursts of generalized paroxysmal fast activity, and there are no tonic seizures (Arzimanoglou et al., 2009). Seizure remission usually is achieved by adolescence, although not all patients are cognitively normal. Seizure and social outcomes for patients with SGE, including LGS The long-term outcome for patients with LGS is notoriously poor, and complete seizure freedom is unusual (Dulac & NGuyen, 1993; Goldsmith et al., 2000; Beaumanoir & Blume, 2005; Arzimanoglou et al., 2009; Hancock & Cross, 2009). This information is derived primarily from case series of LGS patients or populationEpilepsia, 52(Suppl. 5):39, 2011 doi: 10.1111/j.1528-1167.2011.03177.x

based studies that combine LGS patients with others who had childhood-onset SGEs (Sillanp et al., 1998; Camfield & Camfield, 2008). The Nova Scotia population-based study investigated long-term outcomes in 80 children with SGE, including 17 cases of LGS (Camfield & Camfield, 2007, 2008). SGE was defined as an epilepsy disorder with an interictal EEG with generalized spike waves (slow or irregular) and/or multifocal spikes and more than one generalized seizure type including myoclonus, akinetic/atonic, tonic, or atypical absence. Length of follow-up averaged 20 6.5 years, and 59% of patients had their first seizures during the first year of life (Camfield & Camfield, 2007). Within 20 years of diagnosis, approximately 25% of children with SGE died at an average age of 12 years, and at the end of follow-up 39% had intractable epilepsy. A terminal remission of 5 years was seen in 28% of the subjects, most of whom had West syndrome. At the end of follow-up, 94% of those with LGS had intractable epilepsy, significantly more than in those with other SGE syndromes (p < 0.001) (Camfield & Camfield, 2007). Other data from this cohort documented the social outcome of the 52 patients with SGE who survived and were >18 years of age at the end of follow-up (Camfield & Camfield, 2008). Thirteen percent had a good outcome, defined as being capable of living independently; 29% had a moderate outcome, defined as being unable to live independently but being independent for most basic activities of daily living; 58% had a poor outcome, defined as being dependent on others for nearly all activities of daily living. The syndromes associated with a good social outcome (n = 7) were West syndrome and myoclonicastatic epilepsy. Nine patients with LGS were included in the analysis: none had a good social outcome; six had poor social outcome; and three had moderate social outcome. Overall, the evidence indicates that epileptic encephalopathies in childhood (especially LGS) usually are associated with long-term adverse effects on intellectual development, social functioning, and independent living. These unfavorable outcomes must have a profound impact on family members who care for a child with LGS.

Conclusions
LGS is a definable childhood-onset epileptic encephalopathy; however, most of the features used to diagnose LGS are seen in other syndromes. Only the EEG findings of slow spike-wave coupled with bursts of generalized polyspikes in sleep appear to be unique to LGS. Most children with LGS have cognitive stagnation. The reason for this distressing observation is unknown. The observation that cognitive problems may be greatest with earlier onset suggests a profound effect on brain maturation at a critical stage of development. LGS often evolves from other epilepsy syndromes, suggesting that there is an important

9 Denition and Natural History of LGS susceptibility related to a specific stage of brain maturation. Long-term outcome in terms of seizure control and intellectual development are disappointing and can be extraordinarily stressful for families. Seizure control is only one of the important goals in attempting to improve the lives of these special patients. Despite the rarity of LGS, its impact is sufficient to warrant a great deal of further research (Arzimanoglou et al., 2009).
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Disclosures
PRC has nothing to disclose with regard to commercial interests. I confirm that I have read the Journals position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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Epilepsia, 52(Suppl. 5):39, 2011 doi: 10.1111/j.1528-1167.2011.03177.x