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Lennox-Gastaut Syndrome

NORD is very grateful to James W. Wheless, M.D., 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; for assistance in the preparation of this report.

Synonyms of Lennox-Gastaut Syndrome

  • LGS

Disorder Subdivisions

  • No subdivisions found.

General Discussion

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 most recently classified the disorder as an epileptic encephalopathy. Epileptic encephalopathies are a group of disorders in which seizure activity leads to progressive cognitive dysfunction.

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 of the head and face because of sudden, unexpected falls. When sitting, affected individuals may collapsed 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 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 is 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 (psychomotor 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.

In some cases, individuals with Lennox-Gastaut syndrome may have been initially affected by infantile spasms. Infantile spasms, which are also known as West syndrome, are characterized by sudden, involuntary contractions of the head, neck, and trunk and/or uncontrolled extension of the legs and/or arms. (For more on West syndrome, please see the Related Disorders section below.)

Causes

In approximately 70-80 percent of cases, 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), 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 cases of Lennox-Gastaut syndrome no associated condition is present or presumed and the cause of the disorder is unknown.

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 any genes that are 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 any potential genetic factors that are involved in the development of Lennox-Gastaut syndrome.

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 believed 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.

Related Disorders

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 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.)

Standard Therapies

Diagnosis
Lennox-Gastaut syndrome is defined as having a clinical triad that must be identified for a diagnosis. This triad consists of multiple seizures of different types, a distinctive brain wave pattern (slow [1.5- to 2.5-Hz] spike-and-wave pattern) 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). 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 a 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.

Treatment
No specific therapy for Lennox-Gastaut syndrome is effective in all cases and the disorder has proven particularly resistant to most therapeutic options. The three main forms of treatment of Lennox-Gastaut syndrome are anti-epileptic drugs (AEDs), dietary therapy (typically the ketogenic diet) or surgery (VNS therapy or corpus callosotomy).

Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, pediatric neurologists, surgeons, and/or other healthcare professionals may need to systematically and comprehensively plan an affected child's treatment. 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 Lennox-Gastaut syndrome. An affected individual's treatment regimen will need repeated revisions throughout a person's 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).

AEDs are usually given to individuals with Lennox-Gastaut syndrome, but the individual response is highly variable. In some cases, it is possible that treatment with AEDs 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 AEDs. Such medications may include clonazepam, sodium valproate, topiramate, lamotrigine, felbamate (closely monitored), clobazam or rufinamide. However, such drugs may have limited success in treating seizure activity in some individuals with the disorder. In addition, AEDs may be associated with significant side effects, especially in individuals who receive multidrug, high-dose regimens. AEDs can also become less effective over time.

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 or clobazam 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 drug is manufactured by:

Ortho-McNeil Neurologics®
1125 Trenton-Harbourton Road
Titusville, NJ 08560
Phone: 1-800-526-7736

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. The drug is manufactured by Meda Pharmaceuticals, Inc. For more information, contact:

Meda Pharmaceuticals, Inc.
Attn: Felbatol
265 Davidson Ave, Suite 300
Somerset NJ, 08873-4120
Email: info@felbatol.com

In addition, the FDA has approved the orphan 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. For more information, contact:

GlaxoSmithKline Inc.
5 Moore Drive
Research Triangle Park, NC 27709
Phone: 1-888-825-5249

In 2008, the FDA approved a new drug called rufinamide (Banzel) for the use as an adjunctive (add-on) 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. Banzel is manufactured by:

Eisai Inc.
100 Tice Blvd
Woodcliff Lake, NJ 07677
Telephone: 201-692-1100
Finally, clobazam (Onfi) was approved by the FDA in 2011 to treat the seizures associated with Lennox-Gastaut syndrome. Onfi is manufactured by Catalent Pharma Solutions LLC for Lundbeck:
Lundbeck Inc.
Four Parkway North
Deerfield IL 60015
Phone: 866-337-6996
Additional therapies that have been used to treat individuals with Lennox-Gastaut syndrome include the ketogenic diet and various surgical techniques. These options are generally reserved for individuals who do not respond to or no longer respond to drug therapy.

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 and vagus nerve stimulation.

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 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 each individual's needs.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.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:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

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

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

Contact for additional information about Lennox-Gastaut syndrome:

James W Wheless, M.D.
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
51 N Dunlap Avenue, Suite P335
Memphis, TN 38105
901-287-5207 (Suzanne R. Smith)
901-287-5325 (fax)
jwheless@uthsc.edu

Lennox-Gastaut Syndrome Resources

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at solivo@rarediseases.org.)

Other Organizations:

References

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

Rowland LP. Ed. Merritt's Neurology. 10th ed. Lippincott Williams & Wilkins. Philadelphia, PA. 2000:815-816.

Menkes JH, Pine Jr JW, et al. Eds. Textbook of Child Neurology. 5th ed. Williams & Wilkins. Baltimore, MD; 1995:743-744.

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: Dec 16, 2013. Available at: http://emedicine.medscape.com/article/1176735-overview Accessed Jan 28, 2014.

National Institute of Neurological Disorders and Stroke. Lennox-Gastaut Syndrome Information Page. December 30, 2013. Available at: http://www.ninds.nih.gov/disorders/lennoxgastautsyndrome/lennoxgastautsyndrome.htm Accessed Jan 28, 2014.

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Report last updated: 2014/01/28 00:00:00 GMT+0

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