Lennox-Gastaut Syndrome - Symptoms, Causes, Treatment | NORD (2024)

Disease Overview

Lennox-Gastaut syndrome (LGS) is a severe form of epilepsy that typically becomes apparent during infancy or early childhood. Affected children experience several different types of seizures, most commonly atonic, tonic and atypical absence seizures. Children with Lennox-Gastaut syndrome may also develop cognitive dysfunction, delays in reaching developmental milestones and behavioral problems. Lennox-Gastaut syndrome can be caused by a variety of underlying conditions, but in some cases no cause can be identified. Lennox-Gastaut syndrome can be difficult to treat because it is resistant (refractory) to many kinds of antiseizure medications. Research is ongoing to identify and assess new therapies for Lennox-Gastaut syndrome.

There is no consensus in the medical literature on the exact definition of Lennox-Gastaut syndrome. Generally, three findings are necessary for the diagnosis: multiple generalized seizure types; a slow spike-and-wave pattern (less than 2.5 Hz) on EEG; and cognitive dysfunction. The International League Against Epilepsy (ILAE) Task Force recently classified the disorder as a developmental and epileptic encephalopathy (DEE). Developmental and epileptic encephalopathies are a group of disorders in which seizure activity can lead to progressive cognitive dysfunction.

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Synonyms

• LGS

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Signs & Symptoms

The symptoms of Lennox-Gastaut syndrome usually begin during infancy or childhood, most often between 3 to 5 years of age. Multiple types of seizures, which are basically electrical disturbances in the brain, affect children with Lennox-Gastaut syndrome. Most affected individuals experience multiple types of seizures, multiple times throughout the day. As affected individuals grow older, the types and frequency of seizure activity may change.

The most common types of seizures associated with Lennox-Gastaut syndrome are tonic and atonic seizures. Tonic seizures cause increased muscle tone and muscle stiffness. They are characterized by sustained muscle contractions that can cause mild abnormalities such as a slight bend of the body and brief interruption of breathing or more significant problems such as muscle spasms of the face and flexion or extension of the arms and legs. Affected children may extend their arms over their heads similar to a ballet dancer. Tonic seizures are usually brief (lasting between a few seconds and a minute) and are especially prevalent at night during sleep but can also occur during the day. There is usually a brief loss of consciousness during a tonic seizure. Tonic seizures that occur when awake can cause affected individuals to fall.

Atonic seizures cause a sudden loss of muscle tone and limpness. They can cause the head to drop or nod, problems with posture or sudden falls. Atonic seizures are also known as drop attacks. Atonic seizures can lead to injuries to the head and face because of sudden, unexpected falls. When sitting, affected individuals may collapse forward or backward at the waist. Atonic seizures may only partially affect consciousness and usually last only a few seconds.

A third type of seizure commonly associated with Lennox-Gastaut syndrome is atypical absence seizures. This type of seizure is associated with a period of unconsciousness usually marked by unresponsive staring. Absence seizures usually begin and end abruptly and the affected individual usually resumes activity with no memory of the episode. Absence seizures do not cause convulsions and may be so mild that they go unnoticed. They usually last only a couple to several seconds. If the child is developmentally delayed, the parents may only notice a subtle change in function or responsiveness.

Additional types of seizures can affect individuals with Lennox-Gastaut syndrome less often. These include myoclonic seizures, which are characterized by abnormal, jerky movements and may occur alone or in conjunction with atypical absence seizures; tonic-clonic seizures (once known as grand mal seizures), which last a couple of minutes and are characterized by stiffening of the limbs and then jerking of the limbs and face; and partial or focal seizures, which involve electrical abnormalities in a limited area of the brain and come in a variety of forms. Some individuals with Lennox-Gastaut syndrome experience prolonged, uninterrupted seizure activity that lasts for more than 30 minutes (nonconvulsive status epilepticus). Nonconvulsive status epilepticus may be associated with a child being unaware or inattentive and, in some cases, may be so subtle that it goes unnoticed. Nonconvulsive status epilepticus requires medical intervention.

Intelligence is usually, but not always, affected in children with Lennox-Gastaut syndrome. Affected children may experience varying degrees of cognitive dysfunction and delays in reaching developmental milestones such as sitting, crawling or walking. Children with Lennox-Gastaut syndrome may develop normally before the onset of seizures, and then lose previously acquired skills (psychom*otor regression). Because the seizures associated with Lennox-Gastaut syndrome are usually resistant to treatment, intellectual impairment and learning problems may worsen over time. Children with Lennox-Gastaut syndrome may also develop behavioral problems ranging from hyperactivity and irritability to autistic symptoms and psychosis.

Some individuals with Lennox-Gastaut syndrome may have been initially affected by infantile spasms (West syndrome), which are characterized by sudden, involuntary contractions of the head, neck and trunk and/or uncontrolled extension of the legs and/or arms.

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Causes

In approximately 70-80 percent of patients, Lennox-Gastaut syndrome has an identifiable cause. These cases may be referred to as symptomatic Lennox-Gastaut syndrome. Examples of conditions that can cause Lennox-Gastaut syndrome include abnormal development of the brain cortex (cortical dysplasia or other malformations), congenital infections, stroke, trauma, reduced oxygen supply that occurs before birth (perinatal hypoxia), infections of the central nervous system such as encephalitis or meningitis and a rare, genetic disorder called tuberous sclerosis. Approximately 17-30 percent of individuals with Lennox-Gastaut syndrome have a previous history of West syndrome. In general, these cases tend to be more severe.

Lennox-Gastaut syndrome may also be classified as cryptogenic, in which the cause is unknown or cannot be determined after evaluation. Cryptogenic cases are presumed to result from an unidentified condition (secondary Lennox-Gastaut syndrome). Individuals with cryptogenic Lennox-Gastaut syndrome do not have a previous history of seizure activity, prior neurological problems or cognitive impairment before the development of the disorder. Cryptogenic cases generally have a later onset than symptomatic cases.

In some patients, no associated condition is present or presumed and the cause of the disorder is unknown. It is now recommended that children with developmental and epileptic encephalopathies have genetic testing as part of their evaluation for the etiology (or cause) of their disorder. This often reveals a cause.

Although the cause of Lennox-Gastaut is known in most cases, the exact underlying mechanisms that ultimately bring about the various seizures that characterize the disorder are unknown. Researchers have not discovered a single specific gene that is associated with Lennox-Gastaut syndrome, although the disorder may have a genetic component that contributes to its development. More research is necessary to determine the specific factors, including potential genetic factors that are involved in the development of Lennox-Gastaut syndrome.

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Affected populations

Lennox-Gastaut syndrome affects males slightly more often than females. Lennox-Gastaut syndrome is estimated to occur in .1-.28 people per 100,000 and is thought to account for 1-4 percent of all cases of childhood epilepsy. The annual incidence in children is estimated to be 2 per 100,000 children. Onset of Lennox-Gastaut syndrome is usually between 2-7 years with a peak onset between 3 to 5 years.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of Lennox-Gastaut syndrome. Comparisons may be useful for a differential diagnosis.

West syndrome is a type of epilepsy characterized by spasms, an abnormal brain wave pattern (interictal EEG) called hypsarrhythmia and cognitive dysfunction. The spasms that occur may range from violent jackknife or “salaam” movements where the whole body bends in half, or they may be no more than a mild twitching of the shoulder or eye changes. These spasms usually begin in the early months after birth and can sometimes be helped with medication. There are many different causes of West syndrome and if a specific cause can be identified, a diagnosis of symptomatic West syndrome can be made. If a cause cannot be determined, a diagnosis of cryptogenic West syndrome is made. Some infants with West syndrome may eventually develop Lennox-Gestaut syndrome. (For more information on this disorder, choose “West” as your search term in the Rare Disease Database.)

Epilepsy is a general term for a group of neurological disorders characterized by recurrent seizures and associated with abnormal electrical discharges in the brain. It is characterized by loss of consciousness, convulsions, spasms, sensory confusion and disturbances in the autonomic nervous system. Attacks may be preceded by an “aura”, a feeling of unease or sensory discomfort; the aura marks the beginning of the seizure in the brain. This is typically in focal or partial-onset seizures. There are many different types of epilepsy, and the exact cause is generally unknown. Epilepsy can also occur as part of larger syndromes. Types of epilepsy or disorders associated with epilepsy include Rett syndrome, Angleman syndrome, Landau-Kleffner syndrome, Dravet syndrome, and the neuronal ceroid lipofuscinoses. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)

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Diagnosis

Lennox-Gastaut syndrome is defined as having three specific findings that must be identified for a diagnosis. This consists of multiple seizures of different types, a distinctive EEG brain wave pattern (slow [1.5- to 2.5-Hz] spike-and-wave pattern) (Note this pattern may not be present on every EEG.) and some degree of cognitive impairment and behavioral abnormalities. However, these symptoms may not all be present at the onset of the disorder, making an accurate diagnosis of Lennox-Gastaut syndrome difficult. The wide variety of potential causes of Lennox-Gastaut syndrome also complicates the diagnosis.

A diagnosis of Lennox-Gastaut syndrome is usually made based upon a thorough clinical evaluation, a detailed patient history and a complete physical and neurological evaluation including advanced imaging techniques, such as electroencephalography (EEG) and magnetic resonance imaging (MRI). It may take time for all the needed criteria to be present, allowing the diagnosis to be made with certainty. During an EEG, the brain’s electrical impulses are recorded. In individuals with LGS, such EEG testing typically reveals the distinctive brain wave pattern (slow [1.5- to 2.5-Hz] spike-and-wave pattern). During an MRI scan, three-dimensional images are produced that reflect the brain’s anatomy; such scanning helps physicians examine brain structure and potentially locate the cause of the seizure activity. Genetic testing (epilepsy gene panels, whole exome sequencing or whole genome sequencing) that look for genetic causes are starting to become a key part of the evaluation process.

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Standard Therapies

Treatment
No specific therapy for Lennox-Gastaut syndrome is effective in all patients and the disorder is particularly resistant to most therapeutic options. The three main forms of treatment are anti-seizure medications (ASMs), dietary therapy (typically the ketogenic diet) or device/surgery (VNS therapy or corpus callosotomy). Rarely, surgery is an option.

Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, pediatric neurologists, surgeons and/or other healthcare professionals may need to plan an affected child’s treatment systematically and comprehensively. Families need to work with healthcare professionals to develop a treatment plan that covers various potential situations such as seizure emergencies, routine medical illnesses, or what to do if an affected individual misses a dosage of medication. Families should also keep a list of which medications can possibly worsen seizures. An affected individual’s treatment regimen will need repeated revisions throughout their life as the types and frequency of seizures may change, and the effectiveness of a particular therapy can lessen. Other healthcare providers are frequently consulted, including social workers, neuropsychologists, psychiatrists and rehabilitation services (occupational, physical and speech therapy).

ASMs are usually given as first-line therapy to individuals with Lennox-Gastaut syndrome, but the individual response is highly variable. In some patients, it is possible that treatment with ASMs may help reduce or control various types of seizure activity associated with LGS. However, because individuals with Lennox-Gastaut syndrome have different types of seizures, they often require therapy with multiple types of ASMs. Such medications (with formal studies and FDA approval in treating the seizures associated with Lennox-Gastaut syndrome) may include clonazepam, sodium valproate, topiramate, lamotrigine, felbamate (closely monitored), clobazam, rufinamide, cannabidiol or fenfluramine. However, such drugs may have limited success in treating seizure activity in some individuals with the disorder. In addition, ASMs may be associated with significant side effects, especially in individuals who receive multidrug, high-dose regimens. ASMs can also become less effective over time. Being on multiple medications, which may cause sedation, can sometimes worsen seizure control.

Valproate (valproic acid) is generally considered the first-line therapy for Lennox-Gastaut syndrome because it is effective against a wide spectrum of seizures. Valproate is usually first given alone (monotherapy) and if ineffective another drug such as lamotrigine, topiramate, rufinamide, clobazam, cannabidiol or fenfluramine may be added.

A variety of specific drugs have been approved by the Food and Drug Administration (FDA) for the treatment of Lennox-Gastaut syndrome including topiramate (Topamax). Topiramate has been approved as an add-on (adjunctive) therapy for children and adults.

The FDA has also approved the anticonvulsant drug felbamate (Felbatol) for the treatment of seizures in children with Lennox-Gastaut syndrome. Due to the occurrence of rare but serious side effects from the drug, physicians should become familiar with the medication and know how to monitor for side effects before prescribing the medication. This drug, while effective, is not typically first or second line because of the side effect concerns.

The FDA has approved the drug lamotrigine (Lamictal) as an add-on (adjunctive) therapy (i.e., as a medication to be used in association with other appropriate anticonvulsant medications) for the treatment of generalized seizures associated with Lennox-Gastaut syndrome.

In 2008, the FDA approved rufinamide (Banzel) as an add-on (adjunctive) treatment for seizures associated with Lennox-Gastaut syndrome. Rufinamide decreases seizure frequency in some individuals and seems to be particularly effective for atonic or drop attack seizures.

Clobazam (Onfi) was approved by the FDA in 2011 to treat the seizures associated with Lennox-Gastaut syndrome.

In 2018, Epidiolex (cannabidiol or CBD) was approved to treat seizures associated with Lennox-Gastaut syndrome in patients two years of age and older. This is the first FDA-approved drug that contains a purified drug substance derived from theCannabisplant.

In 2022, fenfluramine (Fintepla) was approved to treat seizures associated with Lennox-Gastaut syndrome in patients two years of age and older. This medication requires monitoring of cardiac function every 6 months.

Additional therapies that have been used to treat individuals with Lennox-Gastaut syndrome include the ketogenic diet, VNS Therapy, RNS Therapy (trials are ongoing in 2024, some patients are being treated outside of trials.) and various surgical techniques. These options are generally reserved for individuals who have been treated with at least 2 – 3 FDA approved medications without an adequate response and are typically combined with drug therapy (The exception is dietary therapy, which is typically added to drug therapy, but rarely successful by itself in patients with LGS.).

The ketogenic diet may reduce seizure activity in some individuals with Lennox-Gastaut syndrome. The ketogenic diet is a high fat, low carbohydrate diet that makes the body burn fat for energy instead of sugar (glucose). It is a strict diet that requires rigid compliance and commitment. The ketogenic diet can have side effects and individuals following the diet should be routinely monitored by their physicians and a trained nutritionist. The effectiveness of the ketogenic diet varies from one individual to another. Researchers do not understand why the diet is effective in treating seizures or why it is effective for some people, but not others.

Some individuals with Lennox-Gastaut syndrome, especially those who have not responded to other forms of therapy, may be treated with surgical therapies including complete corpus callosotomy or vagus nerve stimulation, and rarely responsive neurostimulation (RNS).

A corpus callosotomy is a surgical procedure in which the cerebral hemispheres are disconnected by cutting the corpus callosum, which is a large bundle of nerves that connects the two halves (hemispheres) of the brain and allows them to share information. This procedure does not include the cutting of brain tissue. This procedure is generally reserved for individuals who suffer from intractable seizures that lead to injuries (e.g., drop seizures or frequent generalized tonic-clonic seizures) or are potentially life-threatening. It is most effective for atonic, tonic and tonic-clonic seizures.

Vagus nerve stimulation is a procedure in which a device called a pulse generator is inserted into the chest and a wire is run underneath the skin to the vagus nerve in the neck. The pulse generator is similar to a pacemaker and transmits mild, electrical impulses to the brain via the vagus nerve. These impulses prevent seizures from occurring. The intensity and timing of the nerve impulses are determined based upon the needs of the patient. This is combined with drug therapy and most effective for drop seizures and generalized tonic-clonic seizures.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet atwww.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email:[emailprotected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com

For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

Contact for additional information about Lennox-Gastaut syndrome:

James W. Wheless, MD
Professor and Chief of Pediatric Neurology
Le Bonheur Chair in Pediatric Neurology
University of Tennessee Health Science Center
Director, Le Bonheur Comprehensive Epilepsy Program & Neuroscience Institute
Le Bonheur Children’s Hospital
49 N Dunlap Avenue, FOB 3rd Floor
Memphis, TN 38105
901-287-5207 (Wilhelmina Alfonso)
901-287-5325 (fax)
[emailprotected]

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References

TEXTBOOKS
Pellock JM, Nordli DR, Sankar R, Wheless JW (ED’s.) Pellock’s Pediatric Epilepsy, 4th Edition.Demos Medical. NYC, NY. 2017: 451-466.

Acosta MT, Pearl PL. Lennox-Gastaut syndrome. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:549-550.

JOURNAL ARTICLES
Gresham J, Eiland LS, Chung AM. Treating Lennox-Gastaut syndrome in epileptic pediatric patients with third-generation rufinamide. Neuropsychiatr Dis Treat. 2010;6:639-645.

Wheless JW. Managing severe epilepsy syndromes of early childhood. J Child Neurol. 2009;24:24S-32S.

Arzimanoglou A, French J, Blume WT, et al. Lennox-Gastaut syndrome: a consensus approach on diagnosis, assessment, management and trial methodology. Lancet Neurol. 2009;8:82-93.

Stafstrom CE. Update on the management of Lennox-Gastaut syndrome with a focus on rufinamide. Neurophyschiatr Dis Treat. 2009;5:547-551.

Wheless JW, Clarke DF, Arzimanoglou A, Carpenter D. Treatment of pediatric epilepsy: European expert opinion, 2007. Epileptic Disord. 2007;9:353-412.

Markand ON. Lennox-Gastaut syndrome (childhood epileptic encephalopathy). J Clin Neurophysiol. 2003;20:426-441.
Trevathan E. Infantile spasms and Lennox-Gastaut syndrome. J Child Neurol. 2002;17:2S9-2S22.

Frost M, Gates J, Helmers SL, et al. Vagus nerve stimulation in children with refractory seizures associated with Lennox-Gastaut syndrome. Epilepsia. 2001;42:1148-1152.

INTERNET
Cherian KA, Glauser TA, Lennox-Gastaut Syndrome. Medscape. Updated:Aug 6, 2020. Available at: http://emedicine.medscape.com/article/1176735-overviewAccessed April 29, 2024.

National Institute of Neurological Disorders and Stroke. Lennox-Gastaut Syndrome Information Page. Last Update Nov 28, 2023. Available athttps://www.ninds.nih.gov/Disorders/All-Disorders/Lennox-Gastaut-Syndrome-Information-PageAccessed April 29, 2024.

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