Clinical manifestations

Presentation and course

Lennox Gastaut Syndrome is a developmental and epileptic encephalopathy characterized by the presence of (1) multiple types of drug-resistant seizures with onset prior to 18 years (one of which must include tonic); (2) cognitive and often behavioral impairments, which may not be present at seizure onset; and (3) diffuse slow spike-and-wave and generalized paroxysmal fast activity on EEG (137). Symptoms of Lennox-Gastaut syndrome can appear de novo without apparent cause (unknown cause) or result from obvious brain insult (structural/metabolic) or genetic cause (44). The Lennox-Gastaut syndrome is, with rare exception, a condition of infants and children and affects boys more frequently than girls (143; 20). The age of onset is between 2 and 8 years, with peak at 3 to 5 years in most cases overall. In unknown cases, there is a slightly older average age of onset between 6 and 8 years (78). Rarely, late onset forms (onset greater than 10 years of age) have been described (135).

In infants and young children, the earliest sign of Lennox-Gastaut syndrome may be head drops or head nodding, typically prior to onset of walking (20). The walking child usually comes to clinical attention 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 (128).

Tonic seizures, consisting of a sustained increase in axial and limb muscle contraction lasting from 3 seconds to 2 minutes, are mandatory for diagnosis (137). Depending on the extent and groups of muscles involved, they may appear as axial (characterized by flexor movements of the head and trunk), axorhizomelic (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 (54). The seizures may be asymmetrical or predominantly unilateral. Sometimes, automatic behaviors follow the tonic stage. Tonic seizures occur most frequently when falling asleep but may also occur at any time of the day. Tonic seizures are often absent at the onset of epilepsy (20). Subclinical tonic seizures might occur, being revealed only by a sleep EEG recording showing fast bursts of 10 to 12 Hz activity during sleep in association with muscle contraction and may be precipitated by stimuli such as noise, contact, or movement (128).

Atypical absence seizures occur in approximately two thirds of patients. Both the onset and the termination are gradual in contrast to typical absences. Atypical absences are usually long and are often followed by some postictal cognitive impairment. Patients may continue their activity to some degree, as episodes are characterized by "clouding" rather than complete loss of consciousness (54; 20). Associated motor manifestations are more common in atypical than in typical absences and include eyelid or perioral myoclonias, progressive flexion due to loss of postural tone, and localized motor phenomena, such as neck-stiffening or head-nodding (128).

Atonic seizures are characterized by sudden, intense loss of postural tone that involves either the whole body or only the head (128).

Other seizure types, including focal and generalized tonic-clonic seizures, are less frequent (128). Myoclonic seizures may very rarely be seen in Lennox-Gastaut syndrome and may be a prominent feature in children with trisomy 21 (96).

Myoclonic, myoclonic-atonic, atonic, and tonic seizures all cause falls (drop attacks) and are difficult to differentiate clinically from one another without EEG recordings (72). These falls may contribute to recurrent injuries, including lacerations that leave disfiguring scars (128).

About 90% of patients with the Lennox-Gastaut syndrome have one or more episodes of status epilepticus (40). There are various forms, including absence status, which may clinically appear as a state of mild or waxing and waning confusion lasting from days to weeks. Additionally, pure tonic status epilepticus may occur more often in adolescents or adults than children, and in rare reports has been elicited by intravenous administration of benzodiazepines (140).

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 (54). In addition, up to 50% of affected individuals will display behavioral abnormalities such as hyperactivity (most commonly), emotional instability, aggressiveness, destructive behavior, autism, antisocial personality, or hypersexuality (98). 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 (128; 75).

A milder phenotype has been described in eight patients who met the electroclinical diagnostic criteria of Lennox-Gastaut syndrome but without significant cognitive impairment (26). These patients had onset in the second decade of life and had normal neuroimaging.

Neurologic symptoms seen in patients with Lennox-Gastaut syndrome are not specific and are determined by the underlying pathology. Motor signs occur in 59% of cases (98). Seventeen percent of patients have normal neurologic examinations.

Prognosis and complications

The overall prognosis for patients with Lennox-Gastaut syndrome is poor, though variable. A significant majority have cognitive impairment, difficult to control seizures, and deterioration in gait causing them to require assistance in activities of daily living (111). Cognitive impairment usually persists even after seizure control (50). Remission with preserved mentation occurs in few patients; IQ tends to deteriorate with age (111). Features like underlying brain injury, early onset, frequent and slow evolution of seizures, and repeated episodes of status, have a relatively worse prognosis (128).

The slow spike-and-wave pattern tends to resolve over time and focal epileptic discharges (typically multifocal spikes) emerge. Tonic seizures tend to persist, in contrast to myoclonic and atypical absence seizures which are more easily controlled (50).

Clinical vignette

An 8-year-old boy with intellectual disability was developmentally normal until the age of 3 years, when he began having seizures. Initially, he was noted to have frequent falls; later, family noted episodes during sleep of whole body stiffening, screaming, and staring with eyes open. Awake EEG showed 2 to 2.5 Hz spike waves, and sleep recording revealed generalized bursts of polyspikes and paroxysmal fast activity (electrodecremental responses) at times associated with generalized tonic seizures. MRI of the brain was normal. State of the art genetic testing could not be obtained due to financial issues. Seizures, including episodes of atypical absence status epilepticus, persisted despite multiple antiepileptic drugs and a trial of the ketogenic diet. He suffered numerous injuries secondary to drop attacks and wears a helmet at all times. The addition of clobazam to his medication regimen reduced the frequency of drop attacks. The possibility of a surgical procedure (corpus callosotomy) to further reduce the drop attacks is being considered. He attends a specialized school, is in a small class setting, and receives supportive therapies.

Biological basis

Etiology and pathogenesis

In about one quarter to one third of cases, the syndrome develops without antecedent history or evidence of brain pathology and is categorized as Lennox-Gastaut syndrome of “unknown cause” (62; 15; 22). It is likely that genetic or immune-mediated factors account for many of these cases; however, they are as yet unidentified. Clinically, these may be difficult to distinguish from myoclonic-astatic epilepsy.

The other two thirds of cases are “structural/metabolic” and are associated with evidence of brain dysfunction either as an evolution from West syndrome, secondary to acquired structural injury, or associated with an identified metabolic or genetic syndrome.

Between 20% and 40% of patients with Lennox-Gastaut syndrome represent evolution from infantile spasms occurring in infants and young children (54; 13; 111; 143). Likewise, around 25% of patients with infantile spasms will evolve into Lennox-Gastaut syndrome (93; 125). It is rare for patients with infantile spasms to have late-onset Lennox-Gastaut syndrome (62). Patients with infantile spasms and Lennox-Gastaut syndrome nearly always have poorer neurodevelopmental and epilepsy outcomes (40). Four electroclinical patterns have been described during transition from infantile spasms to Lennox-Gastaut syndrome: a) epileptic spasms with multifocal paroxysms, b) focal seizures with focal spike wave discharges in the EEG, c) epileptic spasms and myoclonic seizures with diffuse spike-wave and polyspike wave discharges, and d) mixed pattern (21). In another study, developmental delay and seizures prior to the onset of spasms as well as poor response to first therapeutic agent were found to have a higher risk for transition to Lennox-Gastaut syndrome. Children with unidentified etiologies for spasms had a lower chance to develop Lennox-Gastaut syndrome (105).

Prenatal and perinatal factors have been implicated in “structural/metabolic” Lennox-Gastaut syndrome, namely severe hypoxic ischemic encephalopathy, among others. 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 (98; 100).

Other structural malformations including tuberous sclerosis, porencephaly, and dysembryoplastic neuroepithelial tumor have been associated with the development of Lennox-Gastaut syndrome (124). With the advent of high resolution MRI, cortical dysplasias (127) as well as band heterotopias (12; 63) are being identified as increasingly common substrates of this syndrome as well.

An autoimmune mechanism has been proposed for some cases through case reports of concomitant immune-mediated disorders at epilepsy onset (62), imbalance of human leukocyte antigen (HLA) subtypes (145), and response to steroid and immunoglobulin (73; 144). However, the evidence is still insufficient to support this concept. CSF protein has been found elevated in late-onset Lennox-Gastaut syndrome (onset greater than 10 years of age), suggesting a possible role of inflammation in the pathophysiology in this subset of patients (135).

There has been an increase in research aiming to identify genes associated with Lennox-Gastaut syndrome and other epilepsy syndromes without known etiology. Numerous case reports identify novel gene mutations in patients with Lennox-Gastaut syndrome, and there is evidence that adults with the syndrome have frequent rare copy number variations compared with the general population (94). The Epilepsy Phenome/Genome Project and Epi4K Consortium sequenced 264 probands with either infantile spasms or Lennox-Gastaut syndrome along with their parents in an attempt to identify de novo mutations, identifying at least two (GABRB3 and ALG13) that had not previously been implicated (44). Numerous other genes have been implicated since that time as well, including SCN10A (77), BCL11A (153), ABAT (18), DNM1 (45), KCNB1 (97), KCNT2 (02), dup15 (99), CUX2 (24), PPPC3A (103), and IQSEC2 (25). Rare tandem repeat expansions and copy number variants are also reported in patients with Lennox-Gastaut syndrome (123). Further study is needed to establish more definitive associations and causality, and better therapeutic options in future.

No specific pathophysiological mechanisms have been demonstrated in Lennox-Gastaut syndrome; however, the age range of occurrence suggests that some maturational yet unidentified factors play a determinant role in its development. Although there are various neurologic injuries and conditions noted to precede Lennox-Gastaut syndrome, the syndrome does not develop in all patients with these conditions, and reasons for this are not clearly understood (16).

Hallmark electrophysiologic findings in Lennox-Gastaut syndrome, slow spike wave and paroxysmal fast activity (electrodecremental responses), appear to be mediated by distinct brain networks, the former having primary cortical and subcortical involvement whereas the latter is more diffuse, involving many areas of association cortex as well as simultaneous activation of numerous subcortical structures (118). Studies during deep brain stimulation suggest that cortical electrical activity precedes the electrical activity in the thalamus (30).

Interictal spike-wave activity seems to play a major role in the development of cognitive impairment. This is supported by the observation that cognitive effects are often most profound with earlier onset of disease, as well as by research demonstrating reduced interictal cortical excitability in Lennox-Gastaut syndrome (10).

Although both frontal lobes are thought to be affected, patients have been noted to have an epileptogenic “leading” site in one frontal lobe, with subsequent spread to adjacent cortical areas (17). At the onset of the epilepsy, focal spike-waves and focal discharges are often recorded (71). Subcortical structures may also be involved in the epileptogenic process (146).

Simultaneous EEG-functional MRI studies have demonstrated that the epileptogenic process is driven by the cortex. The generalized paroxysmal fast activity (GPFA), the characteristic EEG signature of Lennox-Gastaut syndrome, has been shown to be initiated by the prefrontal cortex, with propagation to the thalamus via the brainstem. (150). It has also been shown that focal cortical lesions may produce a generalized Lennox-Gastaut syndrome phenotype (149), and lesionectomy can abolish tonic seizures. Lesionectomy in such lesions has been observed to lead to cessation of tonic seizures and abolition of the generalized paroxysmal fast activity (149).

Epidemiology

The incidence of Lennox-Gastaut syndrome is low, each year affecting two in 100,000 children under age 14 (67). Due to the intractable nature of this disorder, the prevalence is somewhat higher, occurring in 1% to 5% of all epilepsies and 3% to 10% of all patients with childhood epilepsy (20). Among children with intellectual disability, around 7% were noted to have Lennox-Gastaut syndrome. The prevalence is higher in institutionalized patients with intellectual disability (16.3%). There is no ethnic or geographic predilection, and boys are more often affected than girls (53; 143).

Prevention

There is no definitive method for prevention of Lennox-Gastaut syndrome as its pathophysiology is not well elucidated. Perhaps effective disease-modifying treatments of epilepsies known to evolve into Lennox-Gastaut syndrome, such as West syndrome, may prevent its occurrence. Additionally, prevention of known underlying etiologies may reduce the incidence of this syndrome.

Differential diagnosis

Lennox-Gastaut syndrome is diagnosed through the combination of defining electrographic patterns and multiple clinical seizures types in a child with cognitive impairment. These features, however, may not all be present at onset and clinical presentation can be highly variable. Therefore, initial differential diagnosis is often broad.

Drop attacks and slow spike-and-wave discharges on EEG may be seen in patients who have conditions other than Lennox-Gastaut syndrome, including overdose of certain antiepileptic medication and focal seizures secondary to structural lesions. Both may produce continuous spike waves in slow sleep (116).

Epilepsy with myoclonic-astatic seizures begins between 2 and 5 years of age with generalized tonic-clonic seizures. This is followed by frequent daily drop attacks due to myoclonic-astatic seizures with atypical absences and perhaps even nonconvulsive status epilepticus (37). The EEG may reveal generalized poly spikes and monomorphic theta rhythms. Two to 3 Hz spike-and-wave discharges and a slow baseline activity may also be noted. Genetic testing may be of help.

Confusing conditions

Late-onset infantile spasms that produce drop attacks may begin in the walking child between 1 and 4 years of age. The drop attacks may be identified as epileptic spasms only by video-EEG recordings of the seizures (14; 41).

Posttraumatic epilepsies and encephalopathy with multifocal epilepsy associated with secondary generalization may produce frontal lobe epilepsy with secondary generalization of the spike-wave activity (128). In these patients, the tonic seizures are usually missing, and onset is at a later age. Additionally, focal frontal lobe seizures that secondarily generalize may produce bilateral tonic features and may be associated with slow generalized spike-wave discharges on EEG as result of rapid spread across the corpus callosum (04).

The syndrome of continuous spike-waves in slow sleep begins between 3 and 6 years of age with atonic seizures and atypical absences with slow spike-waves. However, tonic seizures are not seen (116).

Atypical benign partial epilepsy, or the so called “pseudo-Lennox syndrome,” may be difficult to clinically distinguish from Lennox-Gastaut syndrome. These children, too, present with drop attacks and abnormal EEG often described as “continuous spike-wave of slow sleep.” They do not typically have tonic seizures or paroxysmal fast activity on EEG and course is benign, often remitting in adolescence (64).

Diagnostic workup

The diagnosis is based in part on identifying the combination of several generalized seizure types and other electrographic signatures. Tonic seizures and atypical absences may need ictal EEG recording to be properly identified; irregular slow spike-and-waves may be identified with interictal awake tracing; whereas polyspikes-and-waves are recorded during sleep. Cognitive and behavior deterioration may not be there at onset. The hallmark interictal EEG findings are generalized slow spike-and-wave complexes of less than 2.5 Hz and generalized paroxysmal fast activity.

The interictal EEG reveals slow spike-and-waves consisting of a blunt, slow spike (approximately 150 msec), followed by a slow wave (approximately 350 msec). The amplitude ranges from 200 to 800 microvolts. When two to three 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 (54). These discharges are usually generalized, bilateral, synchronous, and symmetrical, but they may also be asymmetrical and predominant in one hemisphere or one region. The EEG patterns differ among individuals and change from day to day and even moment to moment (54).

During NREM sleep, generalized polyspike discharges or generalized paroxysmal fast activity at 10 c/s lasting 0.5 second or more without obvious clinical correlates are commonly seen. Lower amplitude fast rhythms (electrodecremental responses) may also be associated with subtle seizures or tonic seizures (04). During REM sleep, there is an anterior predominance of the abnormal fast rhythms and polyspike-and-wave complexes, though they are less frequent. During sleep, the abnormal patterns become more symmetrical and synchronous, with even slower spike-and-waves or polyspikes-and-waves. Photic stimulation has no effect on these EEG events (98).

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 (86).

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 (40). 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 (40).

A variety of multifocal or diffuse abnormalities on MRI are found in the structural/metabolic cases. 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, which might improve by a gluten-free diet (120).

Pending further evidence, it will be prudent to undertake a detailed genetic evaluation in children with Lennox-Gastaut syndrome without an identifiable etiology on clinical evaluation and neuroimaging. In children who have associated dysmorphism, a chromosomal microarray might be considered. In children without dysmorphism, genetic panel for epileptic encephalopathy or a whole exome sequencing should be useful.

Management

Treatment for Lennox-Gastaut syndrome is difficult and an optimal approach has not been established. Strategies include antiepileptic medication management as the mainstay; however, vagal nerve stimulator (VNS), resective or disconnective surgeries, specialized diets, and immunotherapy have been used as adjuncts in selected cases.

Drug treatment. A systematic metaanalysis on the pharmacotherapy of Lennox-Gastaut syndrome revealed an overall poor quality of evidence, suggesting the need for future research, considering outcome reporting of overall seizure reduction by applying automated seizure detection devices and the impact on development, cognition, and behavior along with consideration of age-specific efficacy of antiepileptic drugs and of underlying etiologies. Overall, the available data suggested high certainty evidence for overall seizure reduction with lesser chance for adverse events for lamotrigine and rufinamide. The evidence for other add-on antiseizure medications for overall seizure cessation or reduction was low to very low (19). Another metanalysis suggested rufinamide and cannabidiol to have a better efficacy on drop seizures. However, cannabidiol had a higher rate for premature discontinuation compared to placebo and other traditional antiseizure medications (157).

Lamotrigine has been shown to significantly reduce drop attacks (from atonic, tonic, and major myoclonic seizures) as well as generalized tonic-clonic seizures, although atypical absences were not greatly affected (102). This drug should be used with caution and introduced slowly in patients receiving valproate in order to prevent serious rash and Stevens Johnson syndrome (39).

The efficacy of rufinamide in Lennox-Gastaut syndrome was shown in many randomized, placebo-controlled studies (60; 05). The efficacy was shown mainly on tonic-atonic seizures, but reduction was also seen in absence and atypical absence seizures. Moreover, efficacy was maintained long term in an open-label extension study (81). Reductions in seizure frequency were observed throughout this study, with almost 40% of patients presenting 50% or greater reduction in total and tonic-atonic seizure frequency. The most common adverse events were vomiting (30.6%) and pyrexia (25.8%). Similar results have been reported in more recent open-label studies as well (112). A pooled analysis of data from pediatric studies of rufinamide as adjunctive therapy suggests a favorable safety and tolerability profile in this patient population, with somnolence and vomiting being the most common side effects (151). These findings on safety and tolerability have been replicated by other groups as well (108). No negative effects on cognition, adaptive function, and emotional profile were noted in one study (114). In a study on the correlation of the response with etiology and genotypes, it was noted that patients with structural malformation of cortical development had a 40% response rate, whereas patients with mutations in DEPDC5, KCNQ2, MMACHC, and SPATA5 genes achieved greater than 90% of seizure reduction (110).

Carbamazepine and phenytoin can control generalized tonic-clonic convulsions and reduce tonic seizures. However, these drugs may also exacerbate atypical absence seizures (70). Valproate offers a chance for improvement of all seizure types with a single drug. However, the therapeutic response of valproate may be transient in many cases. In addition, this drug has an increased potential for hepatic dysfunction and pancreatitis with polytherapy (66).

The benzodiazepine class has long been under consideration for use in maintenance therapy in Lennox-Gastaut syndrome. Examples of the 1,4-benzodiazepine class include nitrazepam, clonazepam, diazepam, and lorazepam, which have been shown to be effective in some small uncontrolled trials (23; 04). Clobazam, in the 1,5-benzodiazepine class, was shown to significantly reduce drop attacks and some nondrop seizures, though tonic seizures (140), behavior problems, and sedation may be worsened (27). A double-blind, placebo-controlled trial assessed the effect of low dose and high dose clobazam on drop attacks in patients with Lennox-Gastaut syndrome. This study revealed that 56% of patients on low dose clobazam had a reduction of at least 25% in the number of drop attacks compared with 89% of patients in the high dose group (27). The phase 3 study compared low, medium, and high dose clobazam against placebo. Results showed a statistically significant decrease in drop attacks when placebo was compared with each of the three clobazam groups. They found a linear trend of increasing efficacy with increasing dosage (106) and subsequent studies have confirmed a dose-dependent improvement in seizure control (74). Tolerance to clobazam has been reported in a significant proportion of patients (89). Topiramate has been shown in several double-blind trials to significantly reduce the frequency of drop attacks and generalized tonic-clonic seizures when used as an adjunctive treatment in patients with Lennox-Gastaut syndrome (129; 61). However, the cognitive side effects of the drug may cause significant disability in these patients, making it intolerable (59).

Felbamate has been reported to reduce the frequency and severity of drop attacks (48; 09) and other seizure types (76) and can improve behavior in some patients (56). Patient quality of life improved overall in patients on felbamate due to improved level of alertness and verbal responsiveness (48). Though effective in these patients, this drug is associated with a high incidence of serious side effects such as aplastic anemia and hepatic failure, and thus should be used with caution. It should be used with bimonthly follow-up of transaminases and blood cell counts, restricted to cases resistant to other antiepileptic drugs, and should not be given for long periods if there is no clear response.

Zonisamide has been successfully used as an adjunctive medication in adults with focal epilepsy. It was studied in Lennox-Gastaut syndrome, and patients using this medication as long-term adjunctive treatment were found to have an overall reduction in seizure frequency by more than 50%. Most prominent effects were seen in atonic seizures and myoclonic seizures, though generalized tonic clonic seizures were also reduced (155).

Levetiracetam has been an effective and well-tolerated add-on in children with Lennox-Gastaut syndrome. In an open-label, multicenter clinical trial of levetiracetam in 55 children with Lennox-Gastaut syndrome, 58.2% of the enrolled children had greater than 50% reduction in seizures, and 27.3% became seizure free (80).

Auvin and colleagues studied perampanel as an adjunct treatment in a cohort of 13 pediatric and adolescent patients with Lennox-Gastaut syndrome. After a median of 10.8 months on the treatment, nine out of 13 (69%) achieved greater than 50% reduction in seizure frequency. Four (30%) discontinued treatment for inefficacy (2) or worsening of seizures (2). Adverse effects in the responder group were minimal and managed by tapering the medication dose. This small study suggested that perampanel may be efficacious and fairly well tolerated in Lennox-Gastaut syndrome patients (08). In a retrospective study on adults with Lennox-Gastaut syndrome, add-on perampanel resulted in around 50% reduction in seizures in two thirds of the patients (28). At least one adverse effect was noted in around half of the enrolled patients. Significant adverse events such as irritability, aggressive behavior, and agitation were noted in 34% of the patients.

Cannabidiol is the main nonpsychoactive component of cannabis. It has several mechanisms of action, including enhancing activity of the 5HT1a receptor and the a3 and a1 glycine receptors, among others (117). It has been shown to be anticonvulsant in many animal models (68) and its use has been under study in patients with various intractable epilepsy syndromes including Lennox-Gastaut syndrome. One small retrospective study of patients receiving oral cannabis extract found that eight of nine (89%) of patients with Lennox-Gastaut syndrome had a greater than 50% reduction in seizure frequency after initiating this treatment. This was a significantly higher response rate when compared to patients with Doose syndrome and Dravet syndrome (121). An additional open-label interventional trial was conducted in patients with Lennox-Gastaut syndrome and other intractable epilepsies and found that adverse effects such as diarrhea, somnolence, decreased appetite, fatigue, and convulsion were reported in 79% of patients (32). Significant adverse effects were reported in 30% of patients, though only 12% of patients reported significant events such as status epilepticus, diarrhea, pneumonia, and weight loss, which were thought to be possibly related to the cannabidiol. The median reduction in monthly motor seizures was 36.5%. This trial highlighted the importance of randomized control trials to determine the efficacy of cannabidiol and further assess its safety. The results of the first randomized, double-blind, placebo controlled trial was published and revealed that add-on cannabidiol was efficacious in the treatment of drop seizures in Lennox-Gastaut syndrome patients and was fairly well tolerated (141). Other groups have also corroborated these findings (33). In a post-hoc analysis of two placebo controlled, randomized controlled trials, the efficacy of cannabidiol was noted to appear as early as 6 days after starting titration in the cannabidiol groups compared to placebo. Adverse events tended to persist longer in patients taking cannabidiol compared to controls (122). Sustained reductions in the seizure frequency was noted on long-term studies (115). These results have been replicated in other geographic settings. In a retrospective analysis of 34 patients from Korea, reduction of seizure frequency of 52.9% (greater than 50% reduction in 32.3% of the cases) and 29.4% (more than 50% reduction in 20.6%) was reported at 3 months and 6 months, respectively. No major life-threatening adverse events were noted (84). A synergistic effect with clobazam was reported in patients taking cannabidiol. However, cannabidiol can be efficacious even without concomitant clobazam administration. Adverse events are also found to be more with the combination therapy (34).

With the repurposing of fenfluramine, an appetite suppressant used for weight loss and used as an antiseizure medication, it was found that it may be effective in Dravet syndrome and Lennox-Gastaut syndrome. In a phase II open-label dose finding study on the use of fenfluramine on 13 children with Lennox-Gastaut syndrome, 67% had greater than or equal to 50% reduction in seizures (88). At a dosage of 0.2 to 0.7 mg/kg/day, fenfluramine has shown good safety profile, despite its link to major cardiovascular risk, which prompted its withdrawal from market in 1997. Fenfluramine has been used in association with both first- and second-line medications, whereas its use in monotherapy still needs to be assessed (11). In a multicenter, double-blind, placebo-controlled randomized controlled trial, patients with Lennox Gastaut syndrome were randomized to receive either a 0.7 or 0.2 mg/kg/d (maximum 26 mg/d) dose of fenfluramine or placebo (82). The median percentage reduction in frequency of drop seizures was 26.5 percentage points in the 0.7 mg/kg/d fenfluramine group, 14.2 percentage points in the 0.2 mg/kg/d fenfluramine group, and 7.6 percentage points in the placebo group. In a study that looked at the long-term safety and effectiveness of fenfluramine in patients with Lennox-Gastaut syndrome, it was seen that patients with Lennox-Gastaut syndrome experienced sustained reductions in drop seizure frequency on fenfluramine treatment, especially generalized tonic clonic seizures, which are a key risk factor for sudden unexpected death in epilepsy (83). Fenfluramine was generally well tolerated without significant cardiac complications noted in this study.

A retrospective case series of the use of cenobamate in four adults with Lennox-Gastaut syndrome showed a reduction in baseline seizure frequency, ranging from 25% to 74%, with two patients achieving greater than or equal to 50% seizure reduction (46).

Soticlestat (TAK-935) is a selective inhibitor of cholesterol 24-hydroxylase that has been demonstrated to suppress elevation of extracellular glutamate levels, resulting in reduced hyperexcitability in preclinical studies (109). The ELEKTRA trial is a phase II randomized, double-blind, placebo-controlled study of soticlestat in children with Dravet syndrome and Lennox-Gastaut syndrome (65). Seventeen percent of children with Lennox-Gastaut syndrome had placebo-adjusted median reductions in convulsive and drop seizure frequencies. Vigabatrin, an irreversible inhibitor of GABA transaminase, has yielded variable results (49). Lacosamide induced electroclinical remission in one adult patient with Lennox-Gastaut syndrome. However, she developed severe neuropsychiatric disturbances, suggesting the syndrome of forced normalization, which necessitated the tapering of the drug (113). In one case report, seizures were made worse by the GABA analog gabapentin (148). Other medications such as amantadine (acts on multiple neurotransmitter pathways), tryptophan (an essential amino acid), flumazenil (a GABA antagonist), and imipramine (a tricyclic antidepressant), among others, have had anecdotal and limited success in some patients (40). There is an anecdotal report on the efficacy of the calcium channel blocker verapamil in a patient with Lennox-Gastaut syndrome who was found to have mutations affecting the calcium signaling pathway. This reinforces the importance of genetic diagnosis in developing targeting treatment approaches in patients with this condition (36).

Immunotherapy. Corticosteroid treatment is often used in the epileptic encephalopathies and in Lennox-Gastaut syndrome may be useful at gradually tapered dosages in cases of unknown etiology during periods of worsening in the course of evolution (128). Several case series have reported an approximately 70% rate of seizure freedom in patiens with Lennox-Gastaut syndrome treated with prednisone therapy for short (6-12 weeks) course (134; 154). It is not clear whether these effects would endure after cessation of therapy. Clinical trials of intravenous immunoglobulin have yielded equivocal results (73; 144; 57).

Diet. The ketogenic diet has been used with some success in patients with various intractable epilepsy syndromes. The first blinded study of this method was conducted in 20 children with Lennox-Gastaut syndrome, with significantly reduced seizure frequency in both arms (ketogenic diet group more so than control), perhaps because of fasting within the study design and a small amount of resultant ketosis in the control group. Nevertheless, the study results suggested that some level of ketosis improved seizures in all of these children, possibly in a dose-dependent fashion, further advocating use of the diet in these patients (51). Studies have reaffirmed the efficacy of the ketogenic diet in children with Lennox-Gastaut syndrome, with half of the children started on the diet experiencing greater than 50% reduction in the seizure burden (91; 158). Similar efficacy has been reported with the use of the modified Atkins diet, a less restrictive variant of the ketogenic diet (132). Dietary therapies are found to be useful even in children with Lennox-Gastaut syndrome associated with mitochondrial dysfunction (104).

Surgery. A metaanalysis has comprehensively looked at the currently available data on the efficacy of the different surgical techniques in patients with Lennox-Gastaut syndrome (142).

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 (55). With the advent of new microsurgical techniques and the realization that anterior two-thirds section is sufficient in patients who started in school age, 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 the seizures could reappear following anterior callosotomy (119). Small case series have shown the effectiveness of radiosurgical callosotomy (47; 136) and stereotactic laser callosotomy (139). These techniques are associated with a reduced surgical morbidity.

In rare cases where a stable focus exists in association with EEG abnormalities predominant in one hemisphere, the possibility of a focal resection should be investigated (130). Focal resective surgery has been reported in a few cases (156). In a study of 27 patients with Lennox-Gastaut syndrome who underwent resective surgery, multilobar resection was performed in 10 patients, single lobar resection in 11, and functional hemispherectomies in six patients. Engel class I (seizure-free) outcomes were achieved in 59% of patients and an improved cognition in 63% (90). It has been demonstrated that focal spike wave activity remaining ipsilateral to the MRI lesion and asymmetric generalized slow spike and waves with reduced amplitude ipsilateral to the lesion may potentially predict better surgical prognosis in symptomatic patients with Lennox-Gastaut syndrome (152).

Vagal nerve stimulation (VNS) showed some efficacy, with effects observed on atonic seizures followed closely by tonic seizures and with the least effects on generalized tonic-clonic seizures (95; 52; 79). One paper showed a maintained efficacy on long-term follow-up (median 52 months) (85). Despite some claims based on review of the literature that vagal nerve stimulation and callosotomy give similar results, it has been shown that vagal nerve stimulation was ineffective in the 10 patients with Lennox-Gastaut syndrome and 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 (119). However, a metaanalysis of 480 patients with Lennox-Gastaut syndrome suggested that 54% of patients responded favorably to adjunctive vagal nerve stimulation therapy and that this treatment option was safe and well tolerated (35) .Newer vagal nerve stimulation autostimulation version based on detection of tachycardia might be a better tolerated and effective option compared to the earlier versions of vagal nerve stimulation in children with Lennox Gastaut syndrome (01). There has been an evolving interest in exploring deep brain stimulation as a treatment for epilepsy in Lennox-Gastaut syndrome patients (147). The thalamic centro-median nucleus has been the preferred target of stimulation in patients with Lennox-Gastaut syndrome.

The published ESTEL trial on centromedian thalamic nucleus-deep brain stimulation in adults with Lennox-Gastaut syndrome has shown significant reduction in seizure burden compared to controls. The efficacy was more for electrographic seizures compared to diary recorded clinical events (29). Responsive neurostimulation of the same thalamic nucleus showed a good benefit in two patients with Lennox-Gastaut syndrome and autism (87). In a systematic review and individual patient data analysis of centromedian thalamus deep brain stimulation for Lennox-Gastaut syndrome, 80.9% patients were noted to experience greater than or equal to 50% reduction in seizure frequency, but only 6.4% were seizure free (133). Generalized paroxysmal fast activity has been noted to correlate well with clinical response and can be used as a biomarker of treatment response, and it can also be used for titration of treatment parameters (31).

In a small pilot study, addition of transcranial direct current stimulation to the pharmacological treatment in patients with Lennox-Gastaut syndrome was more effective than pharmacological treatment alone (07). In a pilot study, 10 sessions of adjunctive cathodal transcranial direct current stimulation in combination with pharmacologic treatment in Lennox-Gastaut syndrome was found to reduce tonic and atonic seizure frequency at two months of follow-up (131).

Outcomes

Although there are numerous treatment modalities available for patients with Lennox-Gastaut syndrome, their seizures typically do not remit. Patients may suffer from medication toxicity and side effects and may also be subjected to the surgical risks associated with the above procedures. Other comorbidities include cognitive impairment, behavioral disturbances, autism spectrum disorder, other psychiatric disease, malnutrition, and/or other physical limitations. The incidence and severity of these comorbidities vary depending on the etiology of Lennox-Gastaut syndrome in the individual patient.

It might be possible to identify fairly homogenous groups based on baseline demographic, seizure, and EEG characteristics, which might help in prognostication (06). In patients with uncontrolled convulsions, there is a high risk of sudden unexpected death in epilepsy. Severe seizure related autonomic system imbalance may play a major part in the pathophysiology of sudden unexpected death in epilepsy in patients with Lennox-Gastaut syndrome (69). A population-based study from Germany showed significantly higher mortality rates for patients with Lennox-Gastaut syndrome (2.88%) compared to age matched control population (0.01%) over a 10-year period (138).

Special considerations

Even though it is usually identified in the pediatric age group, Lennox-Gastaut syndrome may persist through adolescence and into adulthood (126). However, the electroclinical features might also evolve from those classically described in children. Specific algorithms have been proposed to address the specific diagnostic and therapeutic challenges in this population (101).