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Lennox-Gastaut syndrome

Lennox-Gastaut syndrome
Author:
Angus Wilfong, MD
Section Editor:
Douglas R Nordli, Jr, MD
Deputy Editor:
John F Dashe, MD, PhD
Literature review current through: Dec 2022. | This topic last updated: Jul 29, 2022.

INTRODUCTION — The Lennox-Gastaut syndrome (LGS) is a lifelong condition associated with the onset of severe seizures in childhood, treatment-resistant epilepsy, and intellectual disability [1,2]. LGS is reviewed in this topic.

Other epilepsy syndromes affecting children are discussed elsewhere. (See "Epilepsy syndromes in children".)

CLASSIFICATION — LGS is considered a severe developmental epileptic encephalopathy, in which seizure activity and epileptic discharges cause or contribute to severe cognitive impairment and behavioral disorders beyond what would be expected from the underlying etiology [3].

ETIOLOGY — LGS has many causes, including genetic disorders, cortical malformations, tumors, neurocutaneous syndromes (eg, tuberous sclerosis complex), encephalopathies following hypoxic-ischemic insults, meningitis, and head injuries [2]. Approximately 40 percent of patients have an unknown etiology, although these children are increasingly found to have genetic disorders, particularly chromosomal syndromes or de novo pathogenic variants [3-5].

Up to 25 percent of children with LGS have a history of infantile spasms. Children with this syndrome are often difficult to manage medically and have a poor seizure and neurologic prognosis. Mortality is also high (standardized mortality ratio [SMR] = 14) [6]. Patients without an identifiable cause usually have a somewhat milder phenotype and less profound functional and neurologic impairment in adulthood [7].

EPIDEMIOLOGY — LGS is an uncommon disorder, with an estimated incidence of 0.1 to 0.3 per 100,000 population, affecting approximately 1 to 2 percent of all patients with epilepsy [5] and accounting for approximately 4 percent of childhood epilepsies [8]. There is a slight male predominance.

CLINICAL FEATURES

Onset — Patients usually present before eight years of age, most commonly between three and five years of age. Some children with LGS begin having seizures before reaching the age of one year, and many cases evolve into LGS from other epilepsy syndromes, particularly West syndrome or infantile spasms.

Many of the characteristic clinical and electroencephalographic (EEG) features of LGS are often absent early in the course or even late in the course and can develop over time, making recognition and diagnosis challenging [3,9].

Seizure types — LGS is characterized by multiple seizure types, particularly tonic and atypical absence seizures. Seizures found in LGS include the following types [3]:

Tonic seizures – These involve periods of sustained (seconds to minutes) increase in contraction of the axial and limb muscles and are most prominent during sleep. Tonic seizures during wakefulness can cause sudden falls (also called drop attacks). Tonic seizures are mandatory for the diagnosis of LGS. (See 'Diagnostic criteria' below.)

Atypical absence seizures – These are characterized by episodes of impaired awareness. The episodes may begin and end gradually, making them difficult to recognize.

Atonic seizures – These involve sudden loss of axial muscle tone, leading to drop attacks. Milder atonic seizures present as head nods.

Myoclonic seizures – These are characterized by sudden, brief (<100 ms) muscle jerks that sometimes cause falls.

Focal impaired awareness seizures – These (previously called complex partial seizures) usually manifest with behavioral arrest, staring, and unresponsiveness that lasts between 30 and 120 seconds.

Generalized tonic-clonic seizures – These begin with bilateral limb and axial muscle contraction (tonic phase) and loss of consciousness followed by bilateral, relatively synchronous rhythmic flexion/extension movements of the limbs (clonic phase); most episodes last one to three minutes. These may be preceded by a build-up of myoclonic seizures or focal seizures.

Nonconvulsive status epilepticus – This condition is characterized by seizure activity that causes impairment of consciousness ranging from mild confusion to coma due to ongoing atypical absence seizures, often with myoclonic and atonic elements and clusters of brief tonic seizures. Periods of nonconvulsive status epilepticus occur in most cases at some stage.

Epileptic spasms – These manifest with symmetric contractions of flexor or extensor axial or limb muscles that vary in pattern, intensity, duration, and extent. Most spasms occur in clusters of 2 to more than 100 over one to several minutes.

Cognitive impairment — Intellectual disability (occasionally progressive) is characteristic of LGS, with or without other neurologic abnormalities. Neurodevelopment may be normal before the first seizure, but many children with LGS have neurodevelopmental impairment before the onset of seizures [3].

Behavioral abnormalities — Behavioral conditions associated with LGS include hyperactivity, aggression, autism spectrum disorder, and sleep disturbance [3].

Clinical course — The course of LGS is notable for developmental plateau or loss of developmental milestones, resulting in moderate to profound intellectual disability [3]. The full expression of the clinical features typically develops over time and may not be present at the time of seizure onset.

EVALUATION AND DIAGNOSIS

Investigations — LGS is a clinical diagnosis; there is no specific biomarker [9]. In addition to a clinical history of nocturnal seizures (not necessarily documented by EEG), a sleep EEG is essential for making the diagnosis of LGS since tonic seizures and generalized paroxysmal fast activity are most prominent during sleep [9]. Brain magnetic resonance imaging (MRI) and genetic testing are useful to determine the etiology.

Metabolic testing may be helpful if the etiology is not identified with neuroimaging or genetic testing [3].

EEG — A generalized, slow (≤2.5 Hz) spike-wave pattern on the interictal EEG is required for the diagnosis and usually has highest amplitude in the frontal region. In addition, the diagnosis requires an EEG showing patterns that include paroxysmal fast activity (10 to 20 Hz) with or without associated clinical tonic seizures, electrographic features that are often activated by sleep or seen exclusively during sleep.

The EEG pattern associated with a tonic seizure is similar to the ictal pattern of an infantile spasm, with an electrodecremental response with or without generalized fast activity. (See "Infantile spasms: Clinical features and diagnosis", section on 'Ictal EEG'.)

Imaging — Brain MRI is necessary to look for structural brain abnormalities (eg, cortical malformations, tumor, tuberous sclerosis complex, hypoxic-ischemic encephalopathy) that may inform the etiology, differential diagnosis, or management of LGS [3,9]. However, an MRI is not essential for making the diagnosis of LGS.

Genetic testing — Genetic testing for LGS should include an epilepsy gene panel and chromosomal microarray; if those are negative, whole-exome sequencing may be helpful in determining the etiology [3,9]. (See 'Etiology' above.)

Diagnostic criteria — Mandatory, exclusionary, and alert criteria for the diagnosis of LGS from the International League Against Epilepsy (ILAE) are the following [3]:

Mandatory criteria:

Tonic seizures

At least one additional seizure type from among the following:

-Atypical absences

-Atonic

-Myoclonic

-Focal impaired awareness

-Generalized tonic-clonic

-Nonconvulsive status epilepticus

-Epileptic spasms

EEG with generalized slow spike-and-wave complexes of <2.5 Hz (or history on prior EEG)

EEG with generalized paroxysmal fast activity in sleep (or history on prior EEG)

Age <18 years at onset

Long-term outcome of drug-resistant epilepsy and mild to profound intellectual disability

Exclusionary criterion:

EEG with persistent focal abnormalities but without generalized spike-and-wave pattern

Alert criteria leading to caution in the diagnosis of LGS:

EEG with an exaggerated photic response at low frequencies, suggesting consideration of CLN2 disease (see "Neuronal ceroid lipofuscinosis")

Age at onset >8 years

Periodic re-evaluation — Since the expression of clinical findings, seizure types, and EEG patterns of LGS can evolve over time, it is useful to periodically re-evaluate patients with suspected LGS, including history, neurologic examination, EEG, and brain MRI (if there is suspicion that findings may have been missed on prior studies) to determine or confirm the diagnosis and guide management [3,9].

DIFFERENTIAL DIAGNOSIS

Infantile spasms – Infantile spasms represent an age-specific convulsive disorder of infancy and early childhood. Spasms are usually symmetric contractions of flexor or extensor axial or limb muscles. They vary in pattern, intensity, duration, and extent. The average duration of an individual spasm is 4 to 10 seconds, but most spasms occur in clusters that may last for several minutes. The triad of infantile spasms, arrest of psychomotor development, and hypsarhythmia is known as West syndrome. Most children with infantile spasms present between three and seven months of age; onset after 18 months is rare. (See "Infantile spasms: Clinical features and diagnosis".)

Infantile spasms/West syndrome may evolve to LGS; differentiating them in the transition period may be difficult. Unlike infantile spasms, the tonic seizures of LGS do not occur in clusters on awakening [3].

Epilepsy with myoclonic-atonic seizures (EMAtS) – The onset of EMAtS is usually in early childhood, with previously normal development in approximately two-thirds of patients [3,10]. The myoclonic-atonic seizures may precipitate drop attacks and thereby resemble LGS [9]. The EEG shows a generalized spike-and-wave pattern that is typically >3 Hz, faster than that seen in LGS (≤2.5 Hz). Unlike LGS, the prognosis of EMAtS is favorable for most patients.

Dravet syndrome – Dravet syndrome is distinguished from LGS by refractory seizures beginning before the age of one year [3]. The most common presenting symptom is a hemiclonic or generalized seizure, often precipitated by fever, in an otherwise healthy infant between five and eight months of age. Between one and five years of age, patients have refractory epilepsy characterized by multiple types of seizures, which may include tonic seizures. Neurologic signs include hypotonia, ataxia, pyramidal signs, myoclonus, and behavioral disturbances. Patients generally have a poor neurodevelopmental outcome. (See "Dravet syndrome: Genetics, clinical features, and diagnosis".)

Developmental and epileptic encephalopathy with spike-wave activation in sleep (DEE-SWAS) – Children with DEE-SWAS exhibit normal or only mildly abnormal development until approximately two to four years of age, when they begin having seizures. Initially, seizures predominately occur out of sleep and are typically unilateral clonic or tonic-clonic. Some seizures may manifest with drop attacks, but tonic seizures are absent; the EEG shows nearly continuous diffuse spike-and-wave activity [3,9]. Additional seizure types may include atonic and atypical absence seizures, occasionally progressing to nonconvulsive status epilepticus. There is typically a marked increase in the frequency and types of seizures within the first few years after seizure onset. This is accompanied by a severe neurocognitive regression that occurs around five to six years of age in most patients. (See "Epilepsy syndromes in children", section on 'Developmental and epileptic encephalopathy with spike-wave activation in sleep (DEE-SWAS)'.)

Ring chromosome 20 syndrome – Ring chromosome 20 syndrome is characterized by a variable age of seizure onset (most often <10 years of age) and drug-resistant epilepsy leading to cognitive decline and behavioral problems [9,11]. Features include nocturnal tonic seizures and nonconvulsive status epilepticus with confusional state of variable duration.

Frontal lobe epilepsy – Certain types of epilepsy involving the frontal lobe may manifest with tonic seizures, atonic seizures, and drop attacks [3,9]. These can usually be differentiated from LGS based upon EEG findings, such as the absence of a slow spike-and-wave pattern, the lack of generalized paroxysmal fast activity, and the presence of persistent asymmetries including focal slowing and attenuation.

Neuronal ceroid lipofuscinosis – Classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) presents between two and four years of age, often in children with previously normal development. Typically, there is speech delay, developmental plateau, or loss of developmental milestones beginning in the second year of life, followed by the development of refractory epilepsy. Seizures are polymorphic and include myoclonic, tonic, atypical absence, and tonic-clonic. Over time, ataxia, refractory nonepileptic myoclonus, and spastic quadriparesis develop. The EEG shows photosensitivity with large-amplitude discharges in response to low-frequency photic stimulation (1 to 5 Hz) [12]. Genetic testing can differentiate this disorder from LGS by detecting pathogenic variants in the TPP1 gene. (See "Neuronal ceroid lipofuscinosis".)

Other metabolic disorders – Additional considerations in the differential diagnosis include sialidosis types I and II, Niemann-Pick disease type C, Gaucher disease, and progressive myoclonic epilepsy.

MANAGEMENT

Approach to antiseizure therapy

Initial therapy — Valproate is the preferred first-line therapy for LGS and is often used with adjunctive therapy [9,13]. We start treatment with valproate monotherapy for most patients with newly diagnosed LGS who are naïve to antiseizure treatment. However, due to teratogenicity, valproate may not be the optimal choice for women of childbearing potential. (See 'Valproate' below.)

For patients with newly diagnosed LGS that has evolved from another type of epilepsy, such as infantile spasms, we continue valproate if the patient is already receiving it. Alternatively, if the patient is being treated with another antiseizure medication, it is reasonable to start valproate therapy and taper the patient off the previous therapy [9].

Adjunctive therapy — Nearly all patients with LGS will require adjunctive (add-on) antiseizure medication therapy [9]. However, the optimal therapy for LGS is uncertain and may depend in part upon the underlying etiology. In addition, medication choices may also be guided by concomitant medications and individual patient comorbidities, such as behavior and weight.

LamotrigineLamotrigine is our preferred first choice as adjunctive therapy for patients with LGS who do not achieve adequate seizure control with valproate monotherapy. When used in combination with valproate, lamotrigine should be started at a low dose and titrated slowly, since valproate inhibits the metabolism of lamotrigine. (See 'Lamotrigine' below.)

Rufinamide – When the combination of valproate and lamotrigine fails to provide sufficient control of seizures, rufinamide is the next preferred choice to use as adjunctive therapy. (See 'Rufinamide' below.)

Others – Alternative adjunctive antiseizure medications with efficacy for LGS include the following, but adverse effects or other concerns may limit their utility:

TopiramateTopiramate has the potential for adverse effects that include cognitive impairment and behavioral problems. (See 'Topiramate' below.)

ClobazamClobazam is best used for short-term seizure exacerbations given the potential for tolerance but may also be used when drop attacks are frequent. (See 'Clobazam' below.)

CannabidiolCannabidiol (pharmaceutical) may be most useful for patients with frequent drop attacks. (See 'Cannabidiol' below.)

FenfluramineFenfluramine has a risk of serious adverse effects (eg, cardiac valve injury and pulmonary hypertension) and is reserved for patients with seizures that are refractory to other antiseizure medications. (See 'Fenfluramine' below.)

FelbamateFelbamate is associated with a risk of aplastic anemia and hepatic failure. It is also reserved for patients who have failed other treatment choices, and only if the potential benefits are likely to outweigh the serious risks. (See 'Felbamate' below.)

Avoid combining more than two antiseizure medications – When adding an adjunctive antiseizure medication, one of the two previous antiseizure medications should be tapered off and discontinued. The use of multiple antiseizure medications increases the risk of adverse effects, drug interactions, and poor adherence to therapy [9]. Additionally, data do not support the efficacy of more than two antiseizure medications used concurrently, with the possible exception that clobazam may be added short term (eg, three to five days) for patients with cluster seizures, nonconvulsive status epilepticus, or sustained absence seizures.

Antiseizure medications

Comparative efficacy — A 2021 systematic review, which was focused on overall seizure reduction, found no randomized controlled trials of antiseizure monotherapy or head-to-head comparisons of antiseizure medications for LGS; the 11 included trials all tested adjunctive antiseizure medication [14]. The review concluded there was high-certainty evidence supporting seizure reduction with add-on lamotrigine and rufinamide, low-certainty evidence for seizure reduction with adjunctive topiramate, and low-certainty evidence that adjunctive felbamate led to little or no benefit for complete seizure freedom. The review concluded that it was uncertain whether adjunctive cannabidiol, cinromide, or clobazam increased seizure freedom.

In the United States, approved antiseizure medications for LGS are lamotrigine, rufinamide, topiramate, clobazam, cannabidiol (pharmaceutical), fenfluramine, and felbamate.

Valproate — Valproate is considered to be first-line for LGS because it is a broad-spectrum antiseizure medication and is unlikely to cause exacerbation of seizures, unlike some other agents (eg, carbamazepine) [9,13,15,16]. However, evidence of efficacy specifically for LGS is limited to observational studies [15-17].

Dosing – The initial dose of valproate is 10 to 15 mg/kg per day in one to three divided doses; the dose may be increased by 5 to 10 mg/kg per day at weekly intervals until seizures are controlled or side effects preclude further increases. Daily doses >250 mg should be given in divided doses. The typical maintenance dose range is 30 to 60 mg/kg per day given in divided doses, dependent upon the formulation: immediate-release oral solution (syrup) and regular capsules have a short half-life and are given in three or four divided doses; sprinkle capsules and delayed-release tablets are given in two divided doses; and extended release tablets are given once daily.

The pharmacology, administration, monitoring parameters, and adverse effects of valproate are discussed in greater detail separately. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Valproate'.)

Lamotrigine — The safety and efficacy of lamotrigine for LGS is supported by findings from two randomized controlled trials [14,18,19].

Dosing – The interactions of lamotrigine with other drugs lead to different dosing regimens, which depend on the patient's concomitant antiseizure medications.

For children ages 2 to 12 years taking valproate, which inhibits lamotrigine glucuronidation, the dose of oral immediate-release lamotrigine for the first two weeks is 0.15 mg/kg per day in one to two divided doses, rounding the dose down to the nearest whole tablet and using 2 mg every other day for patients weighing >6.7 kg and <14 kg. During weeks three and four, the dose may be increased to 0.3 mg/kg per day in one to two divided doses. rounding the dose down to the nearest whole tablet. For maintenance, the dose is titrated to effect; after week four, the dose may be increased every one to two weeks by a calculated increment of 0.3 mg/kg per day rounded down to the nearest whole tablet, which is added to the previously administered daily dose. The usual maintenance is 1 to 5 mg/kg per day in one to two divided doses, with a maximum daily dose of 200 mg/day; when adding lamotrigine to valproic acid alone, the initial target lamotrigine maintenance dose in children is 1 to 3 mg/kg per day, but many patients will require higher doses.

There are different lamotrigine dosing regimens for patients not taking valproate and for patients taking or not taking medications that induce glucuronidation (eg, carbamazepine, phenytoin, phenobarbital, and primidone).

The pharmacology, administration, monitoring parameters, and adverse effects of lamotrigine are reviewed in detail separately. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Lamotrigine'.)

Rufinamide — The efficacy and safety of rufinamide for LGS is based on findings from several randomized controlled trials [14,20-24].

Dosing – For children and adolescents <17 years of age, oral rufinamide is started at 10 mg/kg per day in two equally divided doses; the dose may be increased by 10 mg/kg increments every other day to a target daily dose of 45 mg/kg per day given in two equally divided doses; the maximum daily dose is 3200 mg/day.

For adolescents ≥17 years of age and adults, oral rufinamide is started at 400 to 800 mg/day in two equally divided doses; the dose may be increased by 400 to 800 mg daily every other day to a maximum daily dose of 3200 mg/day in two equally divided doses.

The pharmacology, administration, monitoring parameters, and adverse effects of rufinamide are discussed in detail elsewhere. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Rufinamide'.)

Topiramate — The efficacy and safety of topiramate for LGS is supported by the results of one randomized controlled trial of 98 participants with LGS [25], which a 2021 systematic review considered to provide low-certainty evidence for seizure reduction with adjunctive topiramate [14].

Dosing – The initial dose of immediate-release topiramate for children and adolescents 2 to 16 years of age is 1 to 3 mg/kg per day (maximum dose, 25 mg per dose) administered nightly for one week. The dose is increased at one- to two-week intervals in increments of 1 to 3 mg/kg per day given in two divided doses. The dose is titrated to response; the usual maintenance dose is 5 to 9 mg/kg per day in two divided doses (maximum daily dose, 400 mg/day).

The pharmacology, administration, monitoring parameters, and adverse effects of topiramate are reviewed in detail elsewhere. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Topiramate'.)

Clobazam — Two randomized trials have demonstrated that clobazam may be an effective treatment in children with LGS [24]. In one trial, 217 patients with LGS were randomized to one of four treatment arms: placebo or clobazam 0.25, 0.5, or 1 mg/kg per day [26]. After 12 weeks, a >50 percent reduction in drop seizures was observed in 32, 43, 59, and 78 percent of patients in each respective treatment group, demonstrating a dose-response effect; the differences were statistically significant for the two higher clobazam dose groups versus placebo. In another trial, high-dose clobazam (1 mg/kg per day) was associated with a greater number of patients achieving a >50 percent reduction in drop seizures compared with low-dose clobazam (0.25 mg/kg per day; 83 versus 38 percent) [27].

Dosing – For patients two years of age or older and ≤30 kg body weight, clobazam may be started at 5 mg per day in one dose, typically given at bedtime. The dose may be increased at intervals no shorter than every seven days to a maximum total dose of 20 mg per day; doses >5 mg should be given in divided doses twice daily. However, doses up to 2 mg/kg per day may provide improved seizure control [28].

For patients >30 kg body weight, clobazam may be started at 10 mg in two divided doses and increased in intervals no shorter than every seven days to a maximum total dose of 40 mg per day. However, doses up to 2 mg/kg per day (maximum daily dose, 80 mg/day) may provide improved seizure control.

The pharmacology, administration, monitoring parameters, and adverse effects of clobazam are reviewed in detail separately. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Clobazam'.)

Cannabidiol — Randomized trials have found that cannabidiol (pharmaceutical) treatment can reduce the frequency of drop seizures. In one trial, 225 patients with LGS were randomly assigned to three treatment arms: oral cannabidiol 20 mg/kg, 10 mg/kg, or placebo, given in two divided doses daily for 14 weeks [29]. The median reduction from baseline in drop-seizure frequency for the three treatment arms (cannabidiol 20 mg, 10 mg, and placebo) was 42, 37, and 17 percent, respectively. Similarly, another 14-week randomized trial of 171 patients with LGS found that cannabidiol 20 mg/kg daily reduced monthly drop seizure frequency from baseline by 44 percent, versus 22 percent with placebo [30]. More patients withdrew from the trials because of adverse events with cannabidiol than placebo, most often due to elevated levels of serum aminotransferases. In the trial that compared different doses of cannabidiol, the incidence of adverse events was lower in the 10 mg/kg per day group than the 20 mg/kg per day group [29]. The benefit of cannabidiol was sustained in a long-term, open-label extension study of these trials [31].

The US Food and Drug Administration (FDA) approved cannabidiol for the treatment of seizures associated with LGS and Dravet syndrome in June 2018 [32]. In addition, the UK National Institute for Health and Care Excellence (NICE) guidelines recommend cannabidiol with clobazam as an option for treating seizures associated with LGS for people who are two years of age and older [33]. NICE recommends checking the frequency of drop seizures every six months and stopping cannabidiol if the frequency is not reduced by at least 30 percent when compared with the six months prior to treatment.

Dosing Cannabidiol (pharmaceutical) is an oral solution (100 mg/mL) [34]. The initial pediatric dose is 2.5 mg/kg twice daily by mouth. The dose can be increased after one week to the suggested maintenance dose of 5 mg/kg twice daily and may be increased, if needed for further seizure control, up to a maximum of 10 mg/kg twice daily (total 20 mg/kg per day).

Cannabidiol is a CYP2C19 inhibitor that will increase the serum concentrations of clobazam and its active metabolite [35,36]. Therefore, it is appropriate to reduce the dose of clobazam and monitor clobazam levels when adding cannabidiol to clobazam.

The most common adverse reactions with cannabidiol are diarrhea, somnolence, decreased appetite, transaminase elevations, fatigue, malaise, insomnia and other sleep problems, and infections.

Serum transaminase (alanine aminotransferase [ALT] and aspartate transaminase [AST]) and total bilirubin levels should be obtained at baseline and then at one, three, and six months after starting treatment, and periodically thereafter as clinically indicated, or within one month of change in cannabidiol dosing or with changes in other medications that affect liver function [34]. Cannabidiol should be discontinued or interrupted if symptoms or signs of liver dysfunction develop.

The pharmacology, administration, monitoring parameters, and adverse effects of cannabidiol are discussed in detail elsewhere. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Cannabidiol'.)

Fenfluramine — Fenfluramine was approved by the FDA in March 2022 for the treatment of seizures associated with LGS in patients two years of age and older [37]. Fenfluramine and its metabolite, norfenfluramine, increase extracellular levels of serotonin and exhibit agonist activity at serotonin 5HT-2 receptors. Due to the risk of serious adverse effects (eg, cardiac valve injury and pulmonary hypertension), fenfluramine is likely to be reserved for patients with seizures that are refractory to other antiseizure medications.

Evidence supporting the benefit of fenfluramine for LGS comes from a trial that randomly assigned 263 patients with LGS in a 1:1:1 ratio to high-dose fenfluramine (0.7 mg/kg per day), low-dose fenfluramine (0.2 mg/kg per day), or placebo; nearly all patients in the trial were taking one or more concomitant antiseizure medication (mainly valproate, clobazam, and/or lamotrigine) [38,39]. During the 14-week treatment period, the median percentage decrease from baseline in drop seizure frequency was greater for the high-dose fenfluramine group compared with placebo (23.7 versus 8.7 percent).

Dosing Fenfluramine is an oral solution (2.2 mg/mL). The starting and initial maintenance dose is 0.1 mg/kg given twice daily, which can be increased weekly as needed and tolerated [38]. For patients not on concomitant stiripentol, the recommended maintenance dose of fenfluramine is 0.35 mg/kg twice daily, not to exceed a total daily dose of 26 mg. For rare patients who are taking concomitant stiripentol, the maximum daily maintenance dose of fenfluramine is 0.2 mg/kg twice daily, not to exceed a total daily dose of 17 mg.

The most common adverse effects of fenfluramine include diarrhea, decreased appetite, fatigue, somnolence, and vomiting [38]. Of greater concern, fenfluramine treatment has also been associated with a risk of cardiac valve injury and pulmonary hypertension. In the US, fenfluramine is available only through a risk evaluation and mitigation strategy (REMS) program. Evaluation with echocardiography is required before treatment, every six months during treatment, and once three to six months after treatment to monitor for valvular heart disease and pulmonary hypertension.

Felbamate — The efficacy of felbamate for seizure reduction in LGS is supported by a randomized controlled trial of 73 patients [40]. However, a 2021 systematic review found that adjunctive felbamate led to little or no benefit for complete seizure freedom, based on low-certainty evidence [14].

Dosing – For children ages 2 to 14 years, the initial dose of felbamate is 15 mg/kg per day given in three to four divided doses, increasing by 15 mg/kg per day at weekly intervals based upon response and tolerance, with a maximum total daily dose of 45 mg/kg per day or 3600 mg per day, whichever is less.

The risk of fatal aplastic anemia and liver failure limits the utility of felbamate.

The pharmacology, administration, monitoring parameters, and adverse effects of felbamate are reviewed in detail separately. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Felbamate'.)

Nonpharmacologic treatments for seizures — Because seizures with LGS are medically refractory, other treatment options are often considered:

Ketogenic diet – The ketogenic diet has been helpful in some children with LGS [41-43]. In one case series of 71 children with LGS, 50 percent achieved a greater than 50 percent seizure reduction after six months on the diet, while 23 percent achieved a greater than 90 percent seizure reduction [44]. Seizure freedom was rare, however. (See "Ketogenic dietary therapies for the treatment of epilepsy".)

Vagus nerve stimulation – Vagus nerve stimulation appears to be effective in many patients with LGS, leading to a greater than 50 percent reduction in seizure frequency (particularly for atonic and tonic seizures) as well as shortened seizure duration and reduced number of antiseizure medications prescribed [45-47]. (See "Vagus nerve stimulation therapy for the treatment of epilepsy", section on 'Generalized epilepsies'.)

Surgery – Other surgical options, including corpus callosotomy (targeting drop attacks) or lesional epilepsy surgery in patients with hypothalamic hamartoma, may be considered in some refractory cases [9,47-49]. (See "Seizures and epilepsy in children: Refractory seizures", section on 'Epilepsy surgery'.)

Multidisciplinary care — Patients with LGS should be managed by a multidisciplinary team that can care for the individual medical, educational, psychologic, and social needs, including the transition from pediatric to adult care [9,50].

OUTCOMES — LGS nearly always persists into adulthood with drug-resistant epilepsy, although seizure types and EEG findings may evolve and change with time [9].

SUMMARY AND RECOMMENDATIONS

Classification – The Lennox-Gastaut syndrome (LGS) is a lifelong, severe developmental epileptic encephalopathy associated with the onset of seizures in childhood, treatment-resistant epilepsy, and intellectual disability. (See 'Classification' above.)

Etiology – LGS has many causes, including genetic disorders, cortical malformations, tumors, neurocutaneous syndromes (eg, tuberous sclerosis complex), hypoxic-ischemic insults, meningitis, and head injury. (See 'Etiology' above.)

Clinical features – Children usually present in the first seven years of life with a syndrome characterized by multiple seizure types, particularly tonic and atonic seizures; an atypical, slow spike-wave pattern on EEG; and intellectual disability, often with behavioral impairments. (See 'Clinical features' above.)

Evaluation – LGS is a clinical diagnosis. In addition to a clinical history of nocturnal seizures (not necessarily documented by EEG), a sleep EEG is essential for making the diagnosis of LGS, since tonic seizures and generalized paroxysmal fast activity are most prominent during sleep. A brain MRI and genetic testing are useful to determine the etiology. (See 'Evaluation and diagnosis' above.)

Diagnosis – Criteria for the diagnosis of LGS require the presence of tonic seizures and at least one additional seizure type, an EEG showing generalized slow spike-and-wave complexes of ≤2.5 Hz and generalized paroxysmal fast activity in sleep, onset before age 18 years, and long-term outcome of drug-resistant epilepsy and intellectual disability. (See 'Diagnostic criteria' above.)

Seizure management

Pharmacologic treatment – The first-line antiseizure medication for LGS is valproate. Nearly all patients require adjunctive antiseizure medication therapy (eg, valproate combined with lamotrigine or rufinamide), but we try to avoid combining more than two antiseizure medications. The options for adjunctive therapy are discussed above. (See 'Approach to antiseizure therapy' above and 'Antiseizure medications' above.)

Nonpharmacologic treatment – Seizures in LGS are medically refractory; other treatment options include the ketogenic diet, vagus nerve stimulation, and surgery (eg, corpus callosotomy or surgical resection for select patients). (See 'Nonpharmacologic treatments for seizures' above.)

  1. Arzimanoglou A, French J, Blume WT, et al. Lennox-Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial methodology. Lancet Neurol 2009; 8:82.
  2. Mastrangelo M. Lennox-Gastaut Syndrome: A State of the Art Review. Neuropediatrics 2017; 48:143.
  3. Specchio N, Wirrell EC, Scheffer IE, et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: Position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia 2022; 63:1398.
  4. Epi4K Consortium, Epilepsy Phenome/Genome Project, Allen AS, et al. De novo mutations in epileptic encephalopathies. Nature 2013; 501:217.
  5. Asadi-Pooya AA. Lennox-Gastaut syndrome: a comprehensive review. Neurol Sci 2018; 39:403.
  6. Autry AR, Trevathan E, Van Naarden Braun K, Yeargin-Allsopp M. Increased risk of death among children with Lennox-Gastaut syndrome and infantile spasms. J Child Neurol 2010; 25:441.
  7. Widdess-Walsh P, Dlugos D, Fahlstrom R, et al. Lennox-Gastaut syndrome of unknown cause: phenotypic characteristics of patients in the Epilepsy Phenome/Genome Project. Epilepsia 2013; 54:1898.
  8. Camfield PR. Definition and natural history of Lennox-Gastaut syndrome. Epilepsia 2011; 52 Suppl 5:3.
  9. Cross JH, Auvin S, Falip M, et al. Expert Opinion on the Management of Lennox-Gastaut Syndrome: Treatment Algorithms and Practical Considerations. Front Neurol 2017; 8:505.
  10. Doose H. Myoclonic-astatic epilepsy. Epilepsy Res Suppl 1992; 6:163.
  11. Peron A, Catusi I, Recalcati MP, et al. Ring Chromosome 20 Syndrome: Genetics, Clinical Characteristics, and Overlapping Phenotypes. Front Neurol 2020; 11:613035.
  12. Pampiglione G, Harden A. Neurophysiological identification of a late infantile form of 'neuronal lipidosis'. J Neurol Neurosurg Psychiatry 1973; 36:68.
  13. Montouris G, Aboumatar S, Burdette D, et al. Expert opinion: Proposed diagnostic and treatment algorithms for Lennox-Gastaut syndrome in adult patients. Epilepsy Behav 2020; 110:107146.
  14. Brigo F, Jones K, Eltze C, Matricardi S. Anti-seizure medications for Lennox-Gastaut syndrome. Cochrane Database Syst Rev 2021; 4:CD003277.
  15. Strzelczyk A, Schubert-Bast S. Expanding the Treatment Landscape for Lennox-Gastaut Syndrome: Current and Future Strategies. CNS Drugs 2021; 35:61.
  16. Ferrie CD, Patel A. Treatment of Lennox-Gastaut Syndrome (LGS). Eur J Paediatr Neurol 2009; 13:493.
  17. Covanis A, Gupta AK, Jeavons PM. Sodium valproate: monotherapy and polytherapy. Epilepsia 1982; 23:693.
  18. Motte J, Trevathan E, Arvidsson JF, et al. Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome. Lamictal Lennox-Gastaut Study Group. N Engl J Med 1997; 337:1807.
  19. Eriksson AS, Nergårdh A, Hoppu K. The efficacy of lamotrigine in children and adolescents with refractory generalized epilepsy: a randomized, double-blind, crossover study. Epilepsia 1998; 39:495.
  20. Glauser T, Kluger G, Sachdeo R, et al. Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology 2008; 70:1950.
  21. Arzimanoglou A, Ferreira J, Satlin A, et al. Evaluation of long-term safety, tolerability, and behavioral outcomes with adjunctive rufinamide in pediatric patients (≥1 to <4 years old) with Lennox-Gastaut syndrome: Final results from randomized study 303. Eur J Paediatr Neurol 2019; 23:126.
  22. Arzimanoglou A, Ferreira JA, Satlin A, et al. Safety and pharmacokinetic profile of rufinamide in pediatric patients aged less than 4 years with Lennox-Gastaut syndrome: An interim analysis from a multicenter, randomized, active-controlled, open-label study. Eur J Paediatr Neurol 2016; 20:393.
  23. Ohtsuka Y, Yoshinaga H, Shirasaka Y, et al. Rufinamide as an adjunctive therapy for Lennox-Gastaut syndrome: a randomized double-blind placebo-controlled trial in Japan. Epilepsy Res 2014; 108:1627.
  24. Kanner AM, Ashman E, Gloss D, et al. Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2018; 91:82.
  25. Sachdeo RC, Glauser TA, Ritter F, et al. A double-blind, randomized trial of topiramate in Lennox-Gastaut syndrome. Topiramate YL Study Group. Neurology 1999; 52:1882.
  26. Ng YT, Conry JA, Drummond R, et al. Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome. Neurology 2011; 77:1473.
  27. Conry JA, Ng YT, Paolicchi JM, et al. Clobazam in the treatment of Lennox-Gastaut syndrome. Epilepsia 2009; 50:1158.
  28. Isojarvi J, Gidal BE, Chung S, Wechsler RT. Optimizing clobazam treatment in patients with Lennox-Gastaut syndrome. Epilepsy Behav 2018; 78:149.
  29. Devinsky O, Patel AD, Cross JH, et al. Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome. N Engl J Med 2018; 378:1888.
  30. Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2018; 391:1085.
  31. Patel AD, Mazurkiewicz-Bełdzińska M, Chin RF, et al. Long-term safety and efficacy of add-on cannabidiol in patients with Lennox-Gastaut syndrome: Results of a long-term open-label extension trial. Epilepsia 2021; 62:2228.
  32. U.S. Food & Drug Administration. FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm611046.htm (Accessed on June 28, 2018).
  33. National Institute for Health and Care Excellence. Cannabidiol with clobazam for treating seizures associated with Lennox–Gastaut syndrome. Available at: https://www.nice.org.uk/guidance/ta615 (Accessed on January 13, 2020).
  34. Epidiolex (cannabidiol) prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/210365Orig1s011lbl.pdf (Accessed on August 26, 2022).
  35. Gaston TE, Bebin EM, Cutter GR, et al. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia 2017; 58:1586.
  36. Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia 2015; 56:1246.
  37. U.S. FDA approves FINTEPLA® (fenfluramine) oral solution for treatment of seizures associated with Lennox-Gastaut syndrome (LGS). Available at: https://www.ucb.com/stories-media/Press-Releases/article/US-FDA-Approves-FINTEPLAR-Vfenfluramine-Oral-Solution-for-Treatment-of-Seizures-Associated-with-Lennox-Gastaut-Syndrome-LGS (Accessed on April 05, 2022).
  38. Fenfluramine prescribing information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/212102s003lbl.pdf (Accessed on April 05, 2022).
  39. A study to investigate the efficacy and safety of ZX008 (fenfluramine hydrochloride) as an adjunctive therapy in children and adults with Lennox-Gastaut syndrome. Available at: https://clinicaltrials.gov/ct2/show/results/NCT03355209?view=results (Accessed on April 05, 2022).
  40. Felbamate Study Group in Lennox-Gastaut Syndrome. Efficacy of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut syndrome). N Engl J Med 1993; 328:29.
  41. Freeman JM. The ketogenic diet: additional information from a crossover study. J Child Neurol 2009; 24:509.
  42. Dressler A, Stöcklin B, Reithofer E, et al. Long-term outcome and tolerability of the ketogenic diet in drug-resistant childhood epilepsy--the Austrian experience. Seizure 2010; 19:404.
  43. Freeman JM, Vining EP. Seizures decrease rapidly after fasting: preliminary studies of the ketogenic diet. Arch Pediatr Adolesc Med 1999; 153:946.
  44. Lemmon ME, Terao NN, Ng YT, et al. Efficacy of the ketogenic diet in Lennox-Gastaut syndrome: a retrospective review of one institution's experience and summary of the literature. Dev Med Child Neurol 2012; 54:464.
  45. Kostov K, Kostov H, Taubøll E. Long-term vagus nerve stimulation in the treatment of Lennox-Gastaut syndrome. Epilepsy Behav 2009; 16:321.
  46. Shahwan A, Bailey C, Maxiner W, Harvey AS. Vagus nerve stimulation for refractory epilepsy in children: More to VNS than seizure frequency reduction. Epilepsia 2009; 50:1220.
  47. Thirunavu V, Du R, Wu JY, et al. The role of surgery in the management of Lennox-Gastaut syndrome: A systematic review and meta-analysis of the clinical evidence. Epilepsia 2021; 62:888.
  48. Cukiert A, Burattini JA, Mariani PP, et al. Extended, one-stage callosal section for treatment of refractory secondarily generalized epilepsy in patients with Lennox-Gastaut and Lennox-like syndromes. Epilepsia 2006; 47:371.
  49. Pati S, Deep A, Troester MM, et al. Lennox-Gastaut syndrome symptomatic to hypothalamic hamartoma: evolution and long-term outcome following surgery. Pediatr Neurol 2013; 49:25.
  50. Camfield PR, Gibson PA, Douglass LM. Strategies for transitioning to adult care for youth with Lennox-Gastaut syndrome and related disorders. Epilepsia 2011; 52 Suppl 5:21.
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