Lennox-Gastaut syndrome
Encyclopedia
Lennox–Gastaut syndrome (LGS), also known as Lennox syndrome, is a difficult-to-treat form of childhood-onset epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...

 that most often appears between the second and sixth year of life, and is characterized by frequent seizures and different seizure types; it is often accompanied by developmental delay and psychological and behavioral problems.

Characteristics

As a general rule, the age of seizure onset in LGS patients is between the ages of two and six; however, this does not exclude the possibility that seizures can begin before age two, or after age six. The syndrome shows clear parallels to West syndrome
West syndrome
West syndrome or West's Syndrome is an uncommon to rare epileptic disorder in infants. It is named after the English physician, William James West , who first described it in an article published in The Lancet in 1841. The original case actually described his own son, James Edwin West...

, enough to suggest a connection.

Daily multiple seizures are typical in LGS. Also typical is the broad range of seizures that can occur, larger than that of any other epileptic syndrome. The most frequently occurring seizure types are: tonic, which are often nocturnal (90%); the second most frequent are myoclonic seizures, which often occur when the patient is over-tired.

Atonic
Atonic seizure
Atonic seizures , are a type of seizure. They consist of a brief lapse in muscle tone that are caused by temporary alterations in brain function. The seizures are brief - usually less than fifteen seconds. They begin in childhood and may persist into adulthood...

, atypical absence
Absence seizure
Absence seizures are one of several kinds of seizures. These seizures are sometimes referred to as petit mal seizures ....

, complex partial
Complex partial seizure
A complex partial seizure is an epileptic seizure that is associated with bilateral cerebral hemisphere involvement and causes impairment of awareness or responsiveness, i.e. loss of consciousness.-Presentation:...

, focalized and tonic–clonic seizures are also common. Additionally, about half of patients will suffer from status epilepticus
Status epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...

, usually the nonconvulsive type, which is characterized by dizziness, apathy
Apathy
Apathy is a state of indifference, or the suppression of emotions such as concern, excitement, motivation and passion. An apathetic individual has an absence of interest in or concern about emotional, social, spiritual, philosophical or physical life.They may lack a sense of purpose or meaning in...

, and unresponsiveness. The seizures can cause sudden falling (or spasm
Spasm
In medicine a spasm is a sudden, involuntary contraction of a muscle, a group of muscles, or a hollow organ, or a similarly sudden contraction of an orifice. It is sometimes accompanied by a sudden burst of pain, but is usually harmless and ceases after a few minutes...

s in tonic, atonic and myoclonic episodes) and/or loss of balance, which is why patients often wear a helmet to prevent head injury.

In addition to daily multiple seizures of various types, children with LGS frequently have arrested/slowed psycho-motor development and behavior disorders.

The syndrome is also characterized by an interictal (between-seizures) EEG featuring slow spike-wave complexes.

Incidence and prevalence

Approximately 5% of children with epilepsy have LGS, and it is more common in males than females. Whereas some children seem perfectly normal prior to the development of seizures, others already had some form of epilepsy, such as West syndrome, which is seen in 20% of patients before (symptomatic) LGS. West syndrome is characterized by Blitz Nick Salaam seizures, and typically evolves into LGS in the second year of life.

Finland

According to a 1997 community-based retrospective study in the Helsinki metropolitan area and the province of Uusimaa, the annual incidence of Lennox–Gastaut was 2 in 100,000 (0.002%) from 1975–1985.

United States

0.026% of all children in the Atlanta, Georgia
Atlanta, Georgia
Atlanta is the capital and most populous city in the U.S. state of Georgia. According to the 2010 census, Atlanta's population is 420,003. Atlanta is the cultural and economic center of the Atlanta metropolitan area, which is home to 5,268,860 people and is the ninth largest metropolitan area in...

 metropolitan area were estimated to have LGS in 1997, which was defined as, "onset of multiple seizure types before age 11 years, with at least one seizure type resulting in falls, and an EEG
EEG
EEG commonly refers to electroencephalography, a measurement of the electrical activity of the brain.EEG may also refer to:* Emperor Entertainment Group, a Hong Kong-based entertainment company...

 demonstrating slow spike-wave complexes (<2.5 Hz)." The study concluded that LGS accounts for 4% of childhood epilepsies.

Causes

There is no uniform cause: in 20% of the concerned, the LGS develops from the West syndrome
West syndrome
West syndrome or West's Syndrome is an uncommon to rare epileptic disorder in infants. It is named after the English physician, William James West , who first described it in an article published in The Lancet in 1841. The original case actually described his own son, James Edwin West...

. The medical history frequently includes infantile spasms or focalized and generalized seizures.

The most common type of LGS (70–78%) is symptomatic. This does not mean that LGS patients in other categories have no symptoms whatsoever; rather, it means that there is an identifiable underlying pathology responsible. This includes encephalopathy
Encephalopathy
Encephalopathy means disorder or disease of the brain. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of global brain dysfunction; this syndrome can be caused by many different illnesses.-Terminology:...

 (brain damage) or another disease and/or developmental disorder. Frequent causes include tuberous sclerosis
Tuberous sclerosis
Tuberous sclerosis or tuberous sclerosis complex is a rare multi-system genetic disease that causes non-malignant tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, developmental delay, behavioral...

, hereditary metabolic diseases, inflammatory brain disease such as encephalitis
Encephalitis
Encephalitis is an acute inflammation of the brain. Encephalitis with meningitis is known as meningoencephalitis. Symptoms include headache, fever, confusion, drowsiness, and fatigue...

, meningitis
Meningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...

, and toxoplasmosis
Toxoplasmosis
Toxoplasmosis is a parasitic disease caused by the protozoan Toxoplasma gondii. The parasite infects most genera of warm-blooded animals, including humans, but the primary host is the felid family. Animals are infected by eating infected meat, by ingestion of feces of a cat that has itself...

; hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...

ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...

 injury and other birth injuries; and lesion
Lesion
A lesion is any abnormality in the tissue of an organism , usually caused by disease or trauma. Lesion is derived from the Latin word laesio which means injury.- Types :...

s of the frontal lobe
Frontal lobe
The frontal lobe is an area in the brain of humans and other mammals, located at the front of each cerebral hemisphere and positioned anterior to the parietal lobe and superior and anterior to the temporal lobes...

. These patients tend to have a worse prognosis than the idiopathic ones.

In up to one-third of cases no cause can be found. These cases are referred as cryptogenic and/or idiopathic Lennox–Gastaut syndrome. Patients are considered to have idiopathic LGS if they were developing normally prior to the seizures, and cryptogenic if a cause is suspected, but unknown. Not all investigators mention the second category.

Lennox–Gastaut syndrome, drug resistant/drug refractory epilepsy have been recorded with neurovisceral porphyrias including acute intermittent porphyria, hereditary coproporphyria and variegate porphyria. Care must be taken to avoid porphyrinogenic anti-seizure drugs in these cases. Diagnosis may be difficult in children who require enzyme or DNA testing.

Diagnosis

Generally speaking, LGS can often only be defined as a syndrome and/or distinguished from other syndromes because there are various overlaps with other syndromes. Currently, the fact that there is no uniform cause complicates things.
The diagnosis or suspicion of LGS is often a question of probability rather than certainty. This is because the varied presentations of LGS share features with other disorders, many of which may be said to have overlapping characteristics.

The diagnosis is more obvious when the epilepsy has frequent and manifold attacks, with the classic pattern on the electro-encephalogram (EEG); the latter is a slowed rhythm with Spike-wave-pattern, or with a multifocal and generalizing Sharp-slow-wave-discharges at 1.5–2.5 Hz. During sleep, frequently, tonic patterns can be seen. But variations of these patterns are known in patients with no diagnosis other than LGS, and they can differ bilaterally, and from time to time, within the same patient.

General medical investigation usually reveals developmental delay and cognitive deficiencies in children with true LGS. These may precede development of seizures, or require up to two years after the seizures begin, in order to become apparent.

Exclusion of organic or structural brain lesions is also important in establishing a correct diagnosis of LGS; this may require magnetic resonance imaging (MRI) or computerized tomography (CT). An important differential diagnosis is 'Pseudo-Lennox-Syndrome', which differs from LGS, in that there are no tonic seizures; sleeping EEG provides the best basis for distinguishing between the two.

Treatment

LGS seizures are often treatment resistant, but this does not mean that treatment is futile. Options include anticonvulsants, anesthetics, steroids such as prednisone
Prednisone
Prednisone is a synthetic corticosteroid drug that is particularly effective as an immunosuppressant drug. It is used to treat certain inflammatory diseases and some types of cancer, but has significant adverse effects...

, immunoglobulins, and various other pharmacological agents that have been reported to work in individual patients.

Pharmacological

No scientific study has shown any drug to be highly efficacious for treatment of LGS, and its best treatment remains uncertain. Rufinamide
Rufinamide
Rufinamide is an anticonvulsant medication. It is used in combination with other medication and therapy to treat Lennox–Gastaut syndrome and various other seizure disorders...

(Banzel), lamotrigine
Lamotrigine
Lamotrigine, marketed in the US and most of Europe as Lamictal by GlaxoSmithKline, is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. It is also used as an adjunct in treating depression, though this is considered off-label usage...

, topiramate
Topiramate
Topiramate is an anticonvulsant drug. It was originally produced by Ortho-McNeil Neurologics and Noramco, Inc., both divisions of the Johnson & Johnson Corporation. This medication was discovered in 1979 by Bruce E. Maryanoff and Joseph F. Gardocki during their research work at McNeil...

 and felbamate
Felbamate
Felbamate is an anticonvulsant drug used in the treatment of epilepsy. It is used to treat partial seizures in adults and partial and generalized seizures associated with Lennox-Gastaut syndrome in children...

 may help as add-on therapy.
First-line drugs
  • valproates (valproic acid
    Valproic acid
    Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...

    , sodium valproate
    Sodium valproate
    Sodium valproate or valproate sodium is the sodium salt of valproic acid and is an anticonvulsant used in the treatment of epilepsy, anorexia nervosa, panic attack, anxiety disorder, posttraumatic stress disorder, migraine and bipolar disorder, as well as other psychiatric conditions requiring...

     and valproate semisodium
    Valproate semisodium
    Valproate semisodium or divalproex sodium consists of a compound of sodium valproate and valproic acid in a 1:1 molar relationship in an enteric coated form. It is used in the United Kingdom, Canada, and United States for the treatment of the manic episodes of bipolar disorder...

    )
  • felbamate
  • benzodiazepine
    Benzodiazepine
    A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...

    s, specifically clonazepam
    Clonazepam
    Clonazepamis a benzodiazepine drug having anxiolytic, anticonvulsant, muscle relaxant, and hypnotic properties. It is marketed by Roche under the trade name Klonopin in the United States and Rivotril in Australia, Brazil, Canada and Europe...

    , nitrazepam
    Nitrazepam
    Nitrazepam is a type of benzodiazepine drug and is marketed in English-speaking countries under the following brand names: Alodorm, Arem, Insoma, Mogadon, Nitrados, Nitrazadon, Ormodon, Paxadorm, Remnos, and Somnite...

    , and clobazam
    Clobazam
    Clobazam , is a drug which is a benzodiazepine derivative. It has been marketed as an anxiolytic since 1975 and an anticonvulsant since 1984...



Nitrazepam and Clobazam are not approved in the USA.

Clobazam has been recently approved by the FDA on 10/24/11.
Second-line drugs

In 1999, Dr. Sachdeo and colleagues at the University of Medicine and Dentistry of New Jersey and the Robert Wood Johnson Medical School in New Brunswick reported that 33% of the patients in the topiramate
Topiramate
Topiramate is an anticonvulsant drug. It was originally produced by Ortho-McNeil Neurologics and Noramco, Inc., both divisions of the Johnson & Johnson Corporation. This medication was discovered in 1979 by Bruce E. Maryanoff and Joseph F. Gardocki during their research work at McNeil...

 group experienced a minimum 50% reduction in seizures (specifically drop attacks and tonic–clonics), compared with 8% in the placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...

 group. It was also found to be effective as an adjunctive therapy in a review published by Drs. Edith Alva Moncayo and Antonio Ruiz Ruiz in March 2003.

Dr. Motte and colleagues at the American Memorial Hospital at Reims
Reims
Reims , a city in the Champagne-Ardenne region of France, lies east-northeast of Paris. Founded by the Gauls, it became a major city during the period of the Roman Empire....

, France reported in 1997 that lamotrigine
Lamotrigine
Lamotrigine, marketed in the US and most of Europe as Lamictal by GlaxoSmithKline, is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. It is also used as an adjunct in treating depression, though this is considered off-label usage...

 was effective in the treatment of LGS, with the most common side effect in the treatment group relative to placebo being colds or viral illnesses. Two years later, it was approved by Health Canada for adjunctive therapy in Lennox Gastaut in adults and children. The United States Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 approved it for that in August 1998.

Felbamate
Felbamate
Felbamate is an anticonvulsant drug used in the treatment of epilepsy. It is used to treat partial seizures in adults and partial and generalized seizures associated with Lennox-Gastaut syndrome in children...

 is indicated in the use of LGS in the event that everything else fails, and was found to be superior to placebo in controlling treatment resistant partial seizures and atonic seizure
Atonic seizure
Atonic seizures , are a type of seizure. They consist of a brief lapse in muscle tone that are caused by temporary alterations in brain function. The seizures are brief - usually less than fifteen seconds. They begin in childhood and may persist into adulthood...

s. However, it has been known to cause aplastic anemia
Aplastic anemia
Aplastic anemia is a condition where bone marrow does not produce sufficient new cells to replenish blood cells. The condition, per its name, involves both aplasia and anemia...

 and liver toxicity.

Unapproved, off-label, and investigational drugs

Vigabatrin
Vigabatrin
Vigabatrin is an antiepileptic drug that inhibits the catabolism of gamma-aminobutyric acid by irreversibly inhibiting GABA transaminase. It is an analog of GABA, but it is not a receptor agonist...

 was found by Feucht et al. to be an effective add-on in patients whose seizures were not satisfactorily controlled by valproate. Out of 20 children, only 1 experienced a serious side effect (dyskinesia
Dyskinesia
Dyskinesia is a movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or choreia. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but...

).

Zonisamide
Zonisamide
Zonisamide is a sulfonamide anticonvulsant approved for use as an adjunctive therapy in adults with partial-onset seizures for adults; infantile spasm, mixed seizure types of Lennox-Gastaut syndrome, myoclonic, and generalized tonic clonic seizure.-History:...

 showed promise in an overview of controlled and uncontrolled trials conducted in Japan. However, in a physician survey conducted December 2004, only 28% of Lennox–Gastaut and West syndrome
West syndrome
West syndrome or West's Syndrome is an uncommon to rare epileptic disorder in infants. It is named after the English physician, William James West , who first described it in an article published in The Lancet in 1841. The original case actually described his own son, James Edwin West...

 patients improved on zonisamide.

Ketogenic diet

A ketogenic diet
Ketogenic diet
The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that in medicine is used primarily to treat difficult-to-control epilepsy in children. The diet mimics aspects of starvation by forcing the body to burn fats rather than carbohydrates...

 is a diet that causes ketosis
Ketosis
Ketosis is a state of elevated levels of ketone bodies in the body. It is almost always generalized throughout the body, with hyperketonemia, that is, an elevated level of ketone bodies in the blood. Ketone bodies are formed by ketogenesis when the liver glycogen stores are depleted...

, a state in which there is an excessive amount of ketone
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...

s in the body. It is becoming increasingly popular for treating intractable epilepsy.

Intravenous immunoglobulin therapy

Intravenous immunoglobulin therapy has been used in Lennox–Gastaut syndrome as early as 1986, when van Rijckevorsel-Harmant and colleagues used it in seven patients with ostensibly idiopathic LGS and saw EEG improvement and decreased seizure frequency in six of them.

History

LGS was named for neurologists
Neurology
Neurology is a medical specialty dealing with disorders of the nervous system. Specifically, it deals with the diagnosis and treatment of all categories of disease involving the central, peripheral, and autonomic nervous systems, including their coverings, blood vessels, and all effector tissue,...

 William G. Lennox
William G. Lennox
William Gordon Lennox was an American neurologist who was a pioneer in the use of electroencephalography for the diagnosis and treatment of epilepsy.-Biography:...

 (Boston, USA) and Henri Gastaut
Henri Gastaut
Henri Gastaut was a French neurologist.Henri Gastaut was educated in neurology and neuroanatomy at the University of Marseille, graduating M.D. in 1945. In 1953 he became head of the neurobiological laboratories. He was appointed professor of anatomical pathology in 1954 and director of the...

 (Marseille, France).

In 2010 the first documentary highlighting this disorder was produced by Eisai Inc. in cooperation with the LGS Foundation.

http://www.livingwithlgs.com/lgs-documentary.aspx

Resources

LGS Foundation http://www.lgsfoundation.org

Epilepsy.com http://www.epilepsy.com

Epilepsy Foundation http://www.efa.org

See also

  • Epilepsy
    Epilepsy
    Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...

  • West syndrome
    West syndrome
    West syndrome or West's Syndrome is an uncommon to rare epileptic disorder in infants. It is named after the English physician, William James West , who first described it in an article published in The Lancet in 1841. The original case actually described his own son, James Edwin West...

  • Ohtahara syndrome
    Ohtahara syndrome
    Ohtahara syndrome , also known as Early Infantile Epileptic Encephalopathy with Burst-Suppression , is a progressive epileptic encephalopathy. The syndrome is outwardly characterized by tonic spasms and partial seizures, and receives its more elaborate name from the pattern of burst activity on an...

  • Syndromes
  • Epilepsy Phenome/Genome Project
    Epilepsy Phenome/Genome Project
    The Epilepsy Phenome/Genome Project is a government-funded study to identify genes that influence the development of epilepsy and genes that affect the response to treatment. The study involves 25 major epilepsy centers and more than 150 scientists and clinical staff around the United States,...

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