Lennox-Gastaut Syndrome

Practice Essentials

Lennox-Gastaut syndrome (LGS), or childhood epileptic encephalopathy, is a pediatric epilepsy syndrome characterized by multiple seizure types; mental retardation or regression; and abnormal findings on electroencephalography (EEG). See the image below.

View Image

Slow spike wave pattern in a 24-year-old awake male with Lennox-Gastaut syndrome. The slow posterior background rhythm has frequent periods of 2- to 2....

Signs and symptoms

If not present before symptom onset, neurologic and neuropsychologic deficits inevitably appear during the evolution of LGS. Factors associated with more common or more severe mental retardation include the following:

• An identifiable etiology (ie, symptomatic as opposed to cryptogenic LGS)
• A history of West syndrome (infantile spasm)
• Onset of symptoms before age 12-24 months
• More frequent seizures

Average intelligence quotient (IQ) score is significantly lower in patients with symptomatic LGS than in those with cryptogenic LGS. Earlier age of seizure onset is correlated with higher risk of cognitive impairment.

Ictal clinical manifestations include the following:

• Tonic seizures (frequency, 17-95%) - Can occur during wakefulness or sleep but are more frequent during non–rapid eye movement (REM) sleep; may be axial, axiorhizomelic, or global; may be asymmetric
• Atypical absence seizures (frequency, 17-100%) – Can have gradual onset, with incomplete loss of consciousness; associated eyelid myoclonias may be noted
• Atonic, massive myoclonic, and myoclonic-atonic seizures (frequency, 10-56%) – Can all cause a sudden fall, producing injuries, or may be limited to the head falling on the chest; pure atonic seizures are exceptional
• Other types of seizures (generalized tonic-clonic [15%], complex partial [5%], absence status epilepticus, tonic status epilepticus, nonconvulsive status epilepticus)

Findings on general physical examination are normal in many cases. No physical findings are pathognomonic for LGS. Nevertheless, the general physical examination can help identify specific etiologies that have both systemic and neurologic manifestations.

No neurologic examination findings are pathognomonic for LGS. However, neurologic examination of an LGS patient may demonstrate the following:

• Abnormalities in mental status function (specifically, deficits in higher cognitive function consistent with intellectual disability)
• Abnormalities in level of consciousness, cranial nerve function, motor/sensory/reflex examination, cerebellar testing, or gait (nonspecific findings that are more a reflection of the underlying brain injury/abnormality or the effect of anticonvulsant medications)

See Presentation for more detail.

Diagnosis

No laboratory investigations are known to aid in the diagnosis of LGS.

EEG (waking and sleep) is an essential part of the workup. Interictal EEG may demonstrate the following characteristics:

• A slow background that can be constant or transient
• Awake – Diffuse slow spike wave
• Non-REM sleep – Discharges that are more generalized and more frequent, consisting of polyspikes and slow waves
• REM sleep – Decreased spike waves

Ictal EEG may demonstrate the following characteristics:

• Tonic seizure – Diffuse, rapid, low-amplitude activity pattern that progressively decreases in frequency and increases in amplitude; may be preceded by a brief generalized discharge of slow spike waves or flattening of the recording or followed by diffuse slow waves and slow spike waves; no postictal flattening
• Atypical absence seizure – Diffuse, slow, and irregular spike waves; occasionally, discharges of rapid rhythms preceded by flattening of the record for 1-2 seconds, followed by progressive development of irregular fast rhythm in anterior and central regions and ending with brief spike waves
• Atonic, massive myoclonic, or myoclonic-atonic seizure – Slow spike waves, polyspike waves, or rapid diffuse rhythms
• Absence status epilepticus – Continuous spike wave discharges, usually at a lower frequency than at baseline, and rapid rhythms during tonic status epilepticus

Neuroimaging is an important part of the search for an underlying etiology. Modalities include the following:

• Magnetic resonance imaging (MRI) – Generally preferred, may require sedation
• Computed tomography (CT) – Preferred in selected situations, e.g., to assess for acute processes such as hemorrhage or if timely MRI is not available
• Routine positron emission tomography (PET) and single-photon emission CT (SPECT) – Lacking current indications for LGS but may be useful in potential candidates for epilepsy surgery

See Workup for more detail.

Management

Medical treatment options may be divided into the following 3 major groups:

• First-line treatments based on clinical experience or conventional wisdom – valproic acid, benzodiazepines (specifically, clonazepam, nitrazepam, and clobazam; there have been occasional reports of worsening of tonic seizures by benzodiazepines)
• Treatments suspected to be effective on the basis of open-label uncontrolled studies – vigabatrin, zonisamide
• Treatments proven effective by double-blind placebo-controlled studies – lamotrigine, topiramate, felbamate, rufinamide, clobazam, cannabidiol

Surgical options include the following:

• Corpus callosotomy – Effective in reducing drop attacks but not typically helpful for other seizure types; considered palliative rather than curative
• Vagus nerve stimulation – FDA-approved as adjunctive treatment for refractory partial-onset seizures in adults and adolescents older than 12 years
• Focal cortical resection – May improve seizure control in rare cases

Dietary therapies, including the ketogenic diet and modified Atkins diet—involving a high ratio of fats (ketogenic foods) to proteins and carbohydrates (antiketogenic foods)—may be useful in patients with LGS refractory to medical treatment.

See Treatment and Medication for more detail.

• References

Background

Childhood epileptic encephalopathy, or Lennox-Gastaut syndrome (LGS), is a devastating pediatric epilepsy syndrome constituting 1-4% of childhood epilepsies.^[1] The syndrome is characterized by multiple seizure types; mental retardation or regression; and abnormal findings on electroencephalogram (EEG), with paroxysms of fast activity and generalized slow spike-and-wave discharges (1.5-2 Hz).

The most common seizure types are tonic-axial, atonic, and absence seizures, but myoclonic, generalized tonic-clonic, and partial seizures can be observed (see Clinical Presentation). An EEG is an essential part of the workup for LGS. Neuroimaging is an important part of the search for an underlying etiology (see Workup).

A variety of therapeutic approaches are used in LGS, ranging from conventional antiepileptic agents to diet and surgery (see Treatment and Management). Unfortunately, much of the evidence supporting these approaches is not robust, and treatment is often ineffective.

See the following articles for more information:

• First Pediatric Seizure
• Neonatal Seizures
• Pediatric Status Epilepticus
• Benign Childhood Epilepsy
• Benign Neonatal Convulsions
• Juvenile Myoclonic Epilepsy
• Myoclonic Epilepsy Beginning in Infancy or Early Childhood

• References

Pathophysiology

The pathophysiology of LGS is not known. No animal models exist.

A variety of possible pathophysiologies have been proposed. One hypothesis states that excessive permeability in the excitatory interhemispheric pathways in the frontal areas is present when the anterior parts of the brain mature.

Involvement of immunogenetic mechanisms in triggering or maintaining some cases of LGS is hypothesized. Although one study found a strong association between LGS and the human lymphocyte antigen class I antigen B7, a second study did not. No clear-cut or homogeneous metabolic pattern was noted in 2 separate reports of positron emission tomography (PET) studies in children with LGS.

• References

Etiology

LGS can be classified according to its suspected etiology as either idiopathic or symptomatic. Patients may be considered to have idiopathic LGS if normal psychomotor development occurred prior to the onset of symptoms, no underlying disorders or definite presumptive causes are present, and no neurologic or neuroradiologic abnormalities are found. In contrast, symptomatic LGS is diagnosed if a likely cause can be identified as being responsible for the syndrome.

Population-based studies have found that 70-78% of patients with LGS have symptomatic LGS. Underlying pathologies in these cases may include the following:

• Encephalitis and/or meningitis
• Tuberous sclerosis
• Brain malformations (eg, cortical dysplasias)
• Hypoxia-ischemia injury
• Frontal lobe lesions
• Traumatic brain injury

There is a history of infantile spasms in 9-39% of LGS patients.

In addition to idiopathic and symptomatic LGS, some investigators add “cryptogenic” as a third etiologic category.^[2] This category encompasses cases in which the epilepsy appears to be symptomatic but a cause cannot be identified. In an epidemiologic study in Atlanta, Georgia, 44% of patients with LGS were in the cryptogenic group. In a series of 23 patients with cryptogenic LGS, 2.5-47.8% had a family history of epilepsy and febrile seizures.

In 2001, the International League Against Epilepsy (ILAE) Task Force on Classification and Terminology proposed to include LGS among the epileptic encephalopathies. These are conditions in which not only the epileptic activity but also the epileptiform EEG abnormalities themselves are believed to contribute to the progressive disturbance in cerebral function.^[3]

In the revision of the classification of seizures and epilepsy published in 2010, the terms "idiopathic," "symptomatic," and "cryptogenic" were eliminated and replaced by "genetic," "structural/metabolic," and "unknown" to encourage focus on specific underlying mechanisms.^[4] However, many neurologists continue to use those terms as described above.

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Epidemiology

Overall, LGS accounts for 1-4% of patients with childhood epilepsy but 10% of patients with onset of epilepsy when younger than 5 years. The prevalence of LGS in Atlanta, Georgia, was reported as 0.26 per 1000 live births.

LGS is more common in boys than in girls. The prevalence is 0.1 per 1000 population for boys, versus 0.02 per 1000 population for girls (relative risk, 5.31).

The mean age at epilepsy onset is 26-28 months (range, 1 d to 14 y). The peak age at epilepsy onset is older in patients with LGS of an identifiable etiology than in those whose LGS has no identifiable etiology. The difference in age of onset between the group of patients with LGS and a history of West syndrome (infantile spasm) and those with LGS without West syndrome is not significant. The average age at diagnosis of LGS in Japan was 6 years (range, 2-15 y).

Epidemiologic studies in industrialized countries (eg, Israel, Spain, Estonia, Italy, Finland) have demonstrated that the proportion of epileptic patients with LGS seems relatively consistent across the populations studied and similar to that in the United States. The prevalence of LGS is 0.1-0.28 per 1000 population in Europe. The annual incidence of LGS in childhood is approximately 2 per 100,000 children.^[5]

Among children with intellectual disability, 7% have LGS, while 16.3% of institutionalized patients with intellectual disability have LGS.

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Prognosis

Long-term prognosis overall is unfavorable but variable in LGS.^[6] Longitudinal studies have found that a minority of patients with LGS eventually could work normally, but 47-76% still had typical characteristics (mental retardation, treatment-resistant seizures) many years after onset and required significant help (eg, home care, institutionalization).^[7]

Patients with symptomatic LGS, particularly those with an early onset of seizures, prior history of West syndrome, higher frequency of seizures, or constant slow EEG background activity, have a worse prognosis than those with idiopathic seizures.

Tonic seizures may persist and be more difficult to control over time, while myoclonic and atypical absences appear easier to control.

The characteristic diffuse slow spike wave pattern of LGS gradually disappears with age and is replaced by focal epileptic discharges, especially multiple independent spikes.

Mortality rate is reported at 3% (mean follow-up period of 8.5 y) to 7% (mean follow-up period of 9.7 y). Death often is related to accidents. A high rate of injuries is associated with atonic and/or tonic seizures.

The severity of the seizures, frequent injuries, developmental delays, and behavior problems take a large toll on even the strongest parents and family structures. Pay attention to the psychosocial needs of the family (especially siblings). The proper educational setting also is important to help the patient with LGS reach his or her maximal potential.

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Patient Education

Patients and their families need to be informed of the risk for the following severe idiosyncratic reactions from 3 commonly used antiepileptic medications for LGS:

• Valproate - Hepatotoxicity, pancreatitis
• Lamotrigine -Stevens-Johnson syndrome, toxic epidermal necrolysis
• Felbamate - Aplastic anemia, hepatotoxicity

For patient education information, see the Brain and Nervous System Center, as well as Epilepsy.

• References

History

Although approximately 20-30% of children with Lennox-Gastaut syndrome (LGS) are free from neurologic and neuropsychologic deficits prior to onset of symptoms (ie, idiopathic LGS), these problems inevitably appear during the evolution of LGS. Factors associated with more common or more severe mental retardation include the following:

• An identifiable etiology (ie, symptomatic LGS)
• A history of West syndrome (infantile spasm)
• Onset of symptoms before age 12-24 months
• More frequent seizures

Average intelligence quotient (IQ) score is significantly lower in patients with symptomatic LGS than in those with cryptogenic LGS (ie, patients for whom no cause of LGS can be identified but a cause is suspected). In one study, IQ testing showed variable degrees of mental retardation in 66% of the cryptogenic group and in 76% of the symptomatic group at first examination. At the last examination, mental retardation was found in 95% of the cryptogenic group and in 100% of the symptomatic group.

A significant correlation exists between age of onset of seizures and mental deterioration. In one study, almost 98% of the patients who had an onset of seizures before age 2 years had definite cognitive impairment, compared with 63% of those with onset after age 2 years.

Young children with LGS may exhibit mood instability, personality disturbances, or slowing and/or arrest of psychomotor development and educational progress. In contrast, older children with LGS experience character problems, acute psychotic episodes, or chronic forms of psychosis with aggressiveness, irritability, or social isolation.

The most impaired of the cognitive functions are reaction time and information processing, which are prolonged. The main characteristics of mental deterioration are reported as apathy, memory disorders, impaired visuomotor speed, and perseverance.

Ictal clinical manifestations

Tonic seizures have a frequency of 17-95%. These seizures can occur during wakefulness or sleep but are more frequent during non–rapid eye movement (REM) sleep. Duration is from a few seconds to a minute.

Tonic seizures can be axial, axorhizomelic, or global. Axial tonic seizures involve the head and trunk with head and neck flexion, contraction of masticatory muscles, and eventual vocalizations. Axorhizomelic tonic seizures feature tonic involvement of the proximal upper limbs with elevation of the shoulders and abduction of the arms. Global tonic seizures are marked by contraction of the distal part of the extremities, occasionally leading to a sudden fall and at other times mimicking infantile spasms.

Tonic seizures can be asymmetric. Some patients may show gestural automatisms after the tonic phase. The tonic seizure may end in a vibratory component if prolonged.

Atypical absence seizures range in frequency from 17-100%. This wide range results from parental inability to correctly recognize and identify atypical absences. In one study using video/EEG monitoring in a cohort of children with LGS, parental recognition was 27% for atypical absences, while the sensitivity was as high as 80% for myoclonic seizures and 100% for tonic, atonic, tonic-clonic, clonic, and complex partial seizures.

Atypical absences may be difficult to diagnose because their onset may be gradual and loss of consciousness may be incomplete, allowing the patient to continue activities to some degree. Patients may have associated eyelid myoclonias, which are not as rhythmic as in typical absences but often are associated with perioral myoclonias or progressive flexion of the head secondary to a loss of tone. Automatisms may be observed. Seizures may end gradually in some patients and abruptly in others.

Atonic seizures, massive myoclonic seizures, and myoclonic-atonic seizures have a frequency of 10-56% in LGS. These seizures are difficult to differentiate by clinical observation only. Considerable discrepancies exist in the use of these terms. All 3 types can produce a sudden fall, producing injuries (drop attacks, Sturzanfälle) or may be limited to the head falling on the chest (head drop, head nod, nictatio capitis). Pure atonic seizures are exceptional; most have a tonic or myoclonic component.

Other types of seizures are noted. Generalized tonic-clonic seizures are reported in 15% of patients, while complex partial seizures occur in 5%. Absence status epilepticus, tonic status epilepticus, and nonconvulsive status epilepticus all can occur and can be resistant to therapy.

• References

Physical Examination

Findings on general physical examination are normal in many patients with LGS. There are no physical findings pathognomonic for LGS.

Nevertheless, the general physical examination can be important in helping to identify specific etiologies that have both systemic and neurologic manifestations (eg, adenoma sebaceum or ash leaf macules in tuberous sclerosis). Use a Wood lamp to examine the skin. Patients may exhibit moderately severe to severe growth delay, a nonspecific finding that is more a reflection of the underlying brain injury than of a specific epilepsy syndrome.

Neurologic examination

Neurologic examination in patients with LGS demonstrates abnormalities in mental status function, specifically deficits in higher cognitive function consistent with intellectual disability.

Abnormalities in level of consciousness, cranial nerve function, motor/sensory/reflex examination, cerebellar testing, or gait are nonspecific findings and more a reflection of the underlying brain injury or effect of anticonvulsant medications. No neurologic examination findings are pathognomonic for LGS.

• References

Complications

Potential complications of LGS include death (either sudden unexplained death in epilepsy or related to an accident involving a seizure) and injuries (especially facial) from seizures resulting in falls.

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Approach Considerations

Electroencephalography (EEG) is an essential part of the workup for Lennox-Gastaut syndrome (LGS). To date, there are no known laboratory investigations to aid in the diagnosis of LGS. Neuroimaging is an important part of the search for an underlying etiology in a patient with LGS.

• References

Electroencephalography

Always perform an EEG in patients with suspected LGS, since the diagnosis depends on the presence of specific EEG findings. A routine 20-minute EEG may not capture the patient both awake and asleep and thus may miss specific important EEG findings. Instead, obtain prolonged video/EEG telemetry, if possible. Record both waking and sleep EEG, to assist in confirming a suspected diagnosis and to capture and classify each of the patient's multiple seizure types.

Video recordings can also be used to educate the parents on which of the patient's "events" are seizures and which are nonepileptic behavioral events. Parental ability to correctly recognize and identify atypical absences is poor. In one study using video/EEG monitoring in a cohort of children with LGS, parental recognition was 27% for atypical absences, while the sensitivity was as high as 80% for myoclonic seizures and 100% for tonic, atonic, tonic-clonic, clonic, and complex partial seizures.^[8]

Go to EEG in Common Epilepsy Syndromes, Epileptiform Normal Variants on EEG, and Generalized Epilepsies on EEG for more information on these topics.

Interictal electroencephalography

Interictal EEG is characterized by a slow background that can be constant or transient. Permanent slowing of the background is associated with poor cognitive prognosis.

The hallmark of the awake interictal EEG in patients with LGS is the diffuse slow spike wave (see the image below). This pattern consists of bursts of irregular and generalized spikes or sharp waves followed by a sinusoidal 35-400-millisecond slow wave with an amplitude of 200-800 microvolts, which can be symmetric or asymmetric.

The amplitude often is higher in the anterior region or in the frontal or frontocentral areas, but in some patients the activity may dominate in the posterior head regions. The frequency of the slow spike wave activity commonly is found at 1.5-2.5 Hz.

View Image

Slow spike wave pattern in a 24-year-old awake male with Lennox-Gastaut syndrome. The slow posterior background rhythm has frequent periods of 2- to 2....

Slow spike waves usually are not activated by photic stimulation. Hyperventilation rarely induces slow spike waves, although mental retardation prevents adequate cooperation in many patients. During non–rapid eye movement (REM) sleep, discharges are more generalized, more frequent, and consist of polyspikes and slow waves. In REM sleep, spike waves decrease. During periods of frequent seizures, the total duration of REM sleep is reduced.

Ictal electroencephalography

During a tonic seizure, the EEG is characterized by a diffuse, rapid (10-13 Hz), low-amplitude activity pattern, mainly in the anterior and vertex areas ("recruiting rhythm") that progressively decreases in frequency and increases in amplitude.

A brief generalized discharge of slow spike waves or flattening of the recording may precede this pattern. Diffuse slow waves and slow spike waves may follow it.

These fast discharges are common during non-REM sleep. Unlike tonic-clonic seizures, no postictal flattening occurs with these seizures. Clinical manifestations appear 0.5-1 second after the onset of EEG manifestations and last several seconds longer than the discharge.

During an atypical absence seizure, the EEG is characterized by diffuse, slow (2-2.5 Hz), and irregular spike waves, which may be difficult to differentiate from interictal bursts. Occasionally, discharges of rapid rhythms may be observed preceded by flattening of the record for 1-2 seconds, followed by progressive development of irregular fast rhythm in the anterior and central regions, and ending with brief spike waves.

During atonic, massive myoclonic, and myoclonic-atonic seizures, the EEG is characterized by slow spike waves, polyspike waves, or rapid diffuse rhythms. Simultaneous video/EEG recording can help differentiate these seizure types. In most patients, these 3 types of seizures coexist.

The EEG during absence status epilepticus reveals continuous spike wave discharges, usually at a lower frequency than at baseline, and rapid rhythms during tonic status epilepticus.

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Neuroimaging Studies

In general, a magnetic resonance imaging (MRI) scan is the preferred neuroimaging study for a patient with LGS, rather than a CT scan. CT scans may be preferred in selected situations (eg, evaluation of suspected intracranial injury and/or hematoma in a patient with head trauma resulting from a seizure).

Abnormalities revealed by neuroimaging associated with LGS can include findings of tuberous sclerosis, brain malformations (eg, cortical dysplasias), hypoxia-ischemia injury, or frontal lobe lesions.

No current indication exists for routine positron emission tomography (PET) or single-photon emission computed tomography (SPECT) scanning in patients with LGS. However, PET or SPECT scans may be useful in patients undergoing evaluation as candidates for epilepsy surgery.

• References

Approach Considerations

The goals of treatment for patients with Lennox-Gastaut syndrome (LGS) are the same as for all patients with epilepsy: the best quality of life with the fewest seizures (ideally, none), the fewest adverse treatment effects, and the least number of medications.

A variety of therapeutic approaches are used in LGS, ranging from conventional antiepileptic agents to diet and surgery.^[9] Unfortunately, much of the evidence supporting these approaches is not robust, and treatment is often ineffective.^{[10, 11]}

The medical treatment options for patients with LGS can be divided into the following 3 major groups:

• First-line treatments based on clinical experience or conventional wisdom (eg, valproic acid, benzodiazepines [specifically clonazepam, nitrazepam, clobazam^{[12, 13, 14]} ])
• Treatments suspected to be effective on the basis of open-label uncontrolled studies (eg, vigabatrin,^[15] zonisamide^[16] )
• Treatments proven effective by double-blind placebo-controlled studies (eg, lamotrigine,^[17] topiramate,^{[18, 19, 20]} felbamate^[21] , rufinamide^{[22, 23, 24]} , clobazam^[25] , cannabidiol^{[26, 27]} )

The ketogenic diet may be useful in patients with LGS refractory to medical treatment. Surgical options for LGS include corpus callostomy, vagus nerve stimulation, and focal cortical resection.^[28]

• References

Antiepileptic Therapy

Antiepileptic drugs (AEDs) are the mainstay of therapy for patients with LGS. Unfortunately, no one AED gives satisfactory relief for all or even most patients with LGS. A combination of agents frequently is required. Patients with LGS experience frequent exacerbations of their seizures that may require inpatient adjustment of AEDs.

Patients with LGS have a recognized high risk for status epilepticus. Because of the consequent risk of injury or death, a medication for emergency intervention (eg, rectal diazepam) should be prescribed.

Valproate

Valproate (Depakote, Depakene, Depacon) has been considered the first-line treatment option for children with LGS for the past 2 decades. It is reported to be more effective in patients with cryptogenic LGS than in those with symptomatic LGS.

Lamotrigine

The efficacy of lamotrigine (Lamictal) as adjunctive therapy against seizures associated with LGS was demonstrated in 2 controlled trials and multiple open-label studies. This agent is valuable for patients with LGS, despite its risk of idiosyncratic dermatologic reactions, and its use should be considered as soon as diagnosis of LGS is made. Proper attention to concomitant medications, low starting dose, and very slow titration can minimize the risk of dermatologic reactions.

Topiramate

In a multicenter, double-blind, placebo-controlled trial, topiramate (Topamax) was found to be safe and effective as adjunctive therapy for patients with LGS.^[20] The target dose was 6 mg/kg/d. In a long-term open-label extension portion of this trial (mean dosage 10 mg/kg/d), drop attacks were reduced by greater than half in 55% of patients, and 15% of patients were free of drop attacks for over 6 mo at the last visit.^[19]

Felbamate

Felbamate (Felbatol) was found to be safe and effective in patients with LGS in a randomized, double-blind, placebo-controlled adjunctive therapy trial, and 12-month follow-up in patients who completed controlled part of study confirmed long-term efficacy.^[21] Despite the efficacy of felbamate, the significant risk of idiosyncratic reactions associated with its use make it a third-line or fourth-line drug for LGS.

Zonisamide

The effectiveness of zonisamide (Zonegran) in LGS has been investigated in 3 small open-label studies, with promising results. A multicenter study of zonisamide for long-term adjunctive therapy in 62 children with LGS found that it was safe and effective; 4.8% of children had 100% seizure freedom, and 22.6% had >75% reduction in their seizures, independent of seizure type.^[16]

Vigabatrin (Sabril)

Vigabatrin (Sabril) was approved by the US Food and Drug Administration (FDA) in 2009 as monotherapy for infantile spasms in patients 1 month to 2 years old, and as adjunctive therapy for adults with refractory complex partial seizures. In 6 open-label studies involving 78 patients with LGS, 15% became completely seizure free and 44% had a >50% reduction in seizure frequency.^[29]

Rufinamide

The FDA approved rufinamide (Banzel) in 2008 for the adjunctive treatment of seizures associated with LGS in children 4 years and older and adults. In a double-blind, randomized, placebo-controlled trial by Glauser et al, rufinamide produced a statistically significant decrease in total seizure frequency and tonic-atonic seizures in individuals aged 4-30 years.^[22] A 2009 open-label European study also demonstrated decreased seizure frequency amongst those with LGS.^[23]

In a multicenter clinical trial of 59 patients with LGS, rufinamide was found to decrease the frequency of tonic-atonic seizures by 24.2%, versus 3.3% with placebo, and total seizures by 32.9%, versus 3.3% with placebo. Adverse events in the rufinamide group included decreased appetite (17.2%), somnolence (17.2%), and vomiting (13.8%).^[30]

In February 2015, rufinamide was approved in pediatric patients aged 1 to 4 years based on a pharmacokinetic bridging study of a Phase III clinical trial which demonstrated the pharmacokinetic and safety profiles are consistent with those seen in ages ≥ 4 years.^[31]

Benzodiazepines

Clonazepam (Klonopin) is considered an effective first-line AED therapy for seizures associated with LGS. However, the adverse effects and development of tolerance limit its usefulness over time. Dosing on an every-other-day schedule or alternating 2 benzodiazepines daily may slow development of tolerance. The benzodiazepine clobazam, which is widely used as an anticonvulsant in other countries, was approved by the FDA in October 2011.^[14] The combination of valproic acid and a benzodiazepine may be better than either drug alone.

In the CONTAIN study of patients with LGS given clobazam, more than 50% of patients had a 50% or greater decrease in weekly drop- and total-seizure frequency. The percentage of patients achieving 100% reduction in drop seizures was 33% for clobazam-treated patients (vs. 7% for placebo) in Quartile 1 (least severe LGS), and 5% of clobazam-treated patients in Quartile 4 (most severe LGS) achieved 100% reduction in drop seizures, versus 0% for placebo.^[25]

In a second study (OLE study), through 5 years of clobazam therapy, more than 50% of patients in all 4 quartiles (least severe to most severe LGS) demonstrated a decrease of 50% or more in weekly frequency for drop seizures. More than 12% of patients in Quartile 4 achieved 100% reduction in drop seizures from month 3 through year 5.^[25]

The FDA has issued a warning that clobazam, used as add-on therapy to treat seizures in patients with LGS, may trigger Stevens-Johnson syndrome and toxic epidermal necrolysis, rare but potentially fatal cutaneous reactions.^{[32, 33]} The risk of developing these disorders is increased during the first 8 weeks of treatment or when treatment is resumed after it is discontinued. This is not typically seen during clinical practice.

Cannabidiol

The FDA approved a purified formulation of cannabidiol (Epidiolex) in June 2018 for seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) in patients aged 2 years or older. Cannabidiol is a structurally novel anticonvulsant and the exact mechanism by which it produces anticonvulsant effects is unknown. It does not appear to exert its anticonvulsant effects through CB1 receptors, nor through voltage-gated sodium channels.

Approval was based on results from several studies that compared adding cannabidiol added to conventional AEDs to placebo and the incidence of drop seizures from baseline. An international study of 225 patients with LGS (mean patient age 15 years) were randomized to receive cannabidiol 20 mg/kg/day or 10 mg/kg/day, or placebo over 14 weeks. During the 4-week baseline period, the median number of drop seizures was 85 in all groups combined. The median reduction from baseline in drop-seizure frequency per 28 days during the treatment period was 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg group, and 17.2% in the placebo group. During treatment, 30 patients (39%) in the 20-mg group, 26 (36%) in the 10-mg group, and 11 (14%) in the placebo group had at least a 50% reduction from baseline in drop-seizure frequency. The odds ratio (OR) for 20 mg vs placebo was 3.85 (95% CI, 1.75 - 8.47; P < 0.001) and the OR for 10 mg vs placebo was 3.27 (95% CI, 1.47 - 7.26; P = 0.003).^[26]

A study (n=171) conducted in 24 clinical sites in the United States, the Netherlands, and Poland showed a median percentage reduction in monthly drop seizure frequency from baseline was 43.9% (IQR -69.6 to -1.9) in the cannabidiol group and 21.8% (IQR -45.7 to 1.7) in the placebo group. The estimated median difference between the treatment groups was -17.21 (p = 0.0135) during the 14-week treatment period.^[27]

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Corpus Callostomy

Corpus callosotomy is effective in reducing drop attacks but is typically not helpful for other seizure types. It is considered palliative rather than curative. Seizure freedom following corpus callosotomy is rare but can occur.

A 2006 study showed a greater than 90% seizure reduction in 52 of 76 patients with LGS who underwent an extended, one-stage, callosal section (splenium intact); 7 of the 76 patients were seizure free.^[34] The mean follow-up time was 4.7 years. The seizure types most responsive to surgery were atonic and atypical absence.

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Vagus Nerve Stimulation

Vagus nerve stimulation by means of a surgically implanted programmable device is approved by the FDA as an adjunctive treatment for refractory partial-onset seizures in adults and adolescents older than 12 years. In 3 published small studies, approximately three fourths of patients with LGS experienced greater than 50% reduction in seizure frequency with a follow-up period as long as 5 years.^[35]  

A meta-analysis determined that corpus callosotomy has better outcomes than vagus nerve stimulation for atonic seizures, but that vagus stimulation has comparable benefit to corpus callosotomy for all other seizure types.^[36]

• References

Focal Cortical Resection

In rare cases, resection of a localized lesion (eg, vascular lesion, tumor) can improve seizure control in LGS.

• References

Ketogenic Diet

The ketogenic diet comprises a high ratio of fats (ketogenic foods) to proteins and carbohydrates (antiketogenic foods). The ratio of ketogenic to antiketogenic foods in the diet ranges from 2:1 to 4:1 or higher. In general, the benefits of the diet for people with epilepsy include fewer seizures, less drowsiness, better behavior, and need for fewer concomitant AEDs.

Based on multiple open-label and, most recently, randomized controlled studies, the ketogenic diet appears to be a useful therapy for patients with LGS. Efficacy appears greatest for atonic, myoclonic, and atypical absence seizures, but other seizure types (tonic-clonic, secondarily generalized tonic-clonic) may also respond.

In a 2008 randomized controlled trial of the ketogenic diet in children with daily seizures who had a poor response to at least 2 AEDs, 38% of the children in the diet arm had a greater than 50% reduction in seizures. Of the 145 children randomized to the ketogenic diet or control, only 14 had LGS.^[37]

A blinded, crossover study of the ketogenic diet in 20 children with LGS showed a moderate reduction in parent-reported myoclonic-atonic events. Ketosis was not eliminated in the placebo arm; thus, there was no difference observed between the 2 groups regarding reduction in EEG-identified events. When seizure-free patients should be weaned from the diet is not clear.^[38]

The ketogenic diet is not always successful. The following 3 factors are associated with successful implementation of the diet:

• Dedicated, compliant family willing to alter the entire family's lifestyle
• Family able to follow (without wavering) the strict guidelines of the diet
• Team of professionals (centered around a dietitian) trained and experienced in the use of the diet

Potential serious adverse effects include dehydration, clinically significant metabolic acidosis when the diet is initiated, renal stones, cardiac abnormalities, and abnormal lipid profile.

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Injury Prevention

Some patients with LGS wear protective helmets with face guards to maximize protection of the forehead, nose, and teeth (see the image below). Unfortunately, some patients with LGS do not tolerate the helmet with face guards, and even if tolerated, helmets often are uncomfortable and rarely are cosmetically acceptable. Some families are using head guards, which are marketed for concussion prevention in sports; however, these do not necessarily protect the face and teeth.

View Image

Patient with Lennox-Gastaut syndrome wearing a helmet with face guard to protect against facial injury from atonic seizures

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Consultations

Pediatric neuropsychologists can assess intellectual function and educational needs and advise on nonpharmacologic management of behavioral problems. Pediatric psychiatrists can advise on pharmacologic management of behavioral problems. Neurosurgeons can assist in the placement of a vagus nerve stimulator and assess the patient as a candidate for corpus callosotomy or focal resection. Dietitians can assist in the institution and maintenance of the ketogenic diet.

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Medication Summary

The goals of pharmacotherapy in Lennox-Gastaut syndrome (LGS) are to reduce morbidity and prevent complications. Pharmacotherapeutic agents used in such patients include anticonvulsants and benzodiazepines.

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Valproate (Depakote, Depakene, Depacon, Stavzor)

• Dosing, Interactions, etc.

Clinical Context:  Valproate has been considered the first-line treatment option for children with LGS for the past 2 decades. It is reported to be more effective in patients with cryptogenic LGS than in those with symptomatic LGS.

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Lamotrigine (Lamictal, Lamictal ODT, Lamictal XR)

• Dosing, Interactions, etc.

Clinical Context:  Lamotrigine is valuable for patients with LGS despite risk of idiosyncratic dermatologic reactions. Consider it for use as soon as the diagnosis of LGS is made. Proper attention to concomitant medications, a low starting dose, and very slow titration can minimize the risk of dermatologic reactions. The initial dose, maintenance dose, titration intervals, and titration increments depend on concomitant medications.

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Topiramate (Topamax)

• Dosing, Interactions, etc.

Clinical Context:  Topiramate has been found to be safe and effective as adjunctive therapy (target dose 6 mg/kg/d) for patients with LGS.

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Felbamate (Felbatol)

• Dosing, Interactions, etc.

Clinical Context:  Felbamate has been found to be safe and effective in patients with LGS. However the significant risk of idiosyncratic reactions associated with its use make it a third-line or fourth-line drug for LGS.

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Zonisamide (Zonegran)

• Dosing, Interactions, etc.

Clinical Context:  Zonisamide is effective as long-term adjunctive therapy in children with LGS.

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Vigabatrin (Sabril)

• Dosing, Interactions, etc.

Clinical Context:  Vigabatrin was approved by US Food and Drug Administration (FDA) in 2009 as monotherapy for patients with infantile spasms aged 1 month to 2 years and as adjunctive therapy for adults with refractory complex partial seizures.

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Levetiracetam (Keppra, Keppra XR)

• Dosing, Interactions, etc.

Clinical Context:  Levetiracetam is approved by FDA for partial seizures, but may have efficacy against a range of seizure types in LGS.

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Rufinamide (Banzel)

• Dosing, Interactions, etc.

Clinical Context:  An antiepileptic agent that is structurally unrelated to other antiepileptics, rufinamide modulates sodium channel activity, particularly prolongation of the channel's inactive state. It significantly slows sodium channel recovery and limits sustained repetitive firing of sodium-dependent action potentials. It is indicated for adjunctive therapy in adults and children aged 1 year or older with seizures associated with LGS.

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Cannabidiol (Epidiolex)

• Dosing, Interactions, etc.

Clinical Context:  Purified formulation of cannabidiol indicated for treatment of seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) in patients aged 2 years or older. Cannabidiol is a structurally novel anticonvulsant and the exact mechanism by which it produces anticonvulsant effects is unknown. It does not appear to exert its anticonvulsant effects through CB1 receptors, nor through voltage-gated sodium channels.

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Class Summary

These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.

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Clonazepam (Klonopin)

• Dosing, Interactions, etc.

Clinical Context:  Clonazepam is considered an effective first-line AED therapy for seizures associated with LGS. Adverse effects and development of tolerance limit usefulness over time; dosing on an every-other-day schedule or alternating 2 benzodiazepines daily may slow development of tolerance. The benzodiazepine nitrazepam (Mogadon) is not approved by FDA but is available in many countries. The combination of valproic acid and a benzodiazepine may be better than either drug alone.

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Clobazam (ONFI)

• Dosing, Interactions, etc.

Clinical Context:  1,5-benzodiazepine that possesses potent anticonvulsant properties. Exact mechanism of action is not fully understood; thought to potentiate GABAergic neurotransmission resulting from binding to GABA-A receptor. The active metabolite, N-demethylclobazam, is largely responsible for its long duration of action. It is indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients older than 2 years.

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Class Summary

By binding to specific receptor-sites, these agents appear to potentiate the effects of gamma-aminobutyrate (GABA) and facilitate inhibitory GABA neurotransmission and other inhibitory transmitters.

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