Lennox–Gastaut syndrome

Lennox–Gastaut syndrome (LGS) is a childhood-onset epilepsy that most often appears between the second and sixth year of life. LGS is characterized by a triad of signs including frequent seizures of multiple types, an abnormal EEG pattern of less than 2.5 Hz slow spike wave activity,^[1] and moderate to severe intellectual impairment.^[2]

Signs and symptoms

The age of onset of seizures is typically between three and five, though onset can occur at an earlier or later age.^[3] The syndrome shows clear parallels to West syndrome, 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 type is tonic seizures, which are often nocturnal (90%); the second most frequent are myoclonic seizures, which often occur when the person is over-tired.^[4]

Atonic, atypical absence, tonic, complex partial, focalized and tonic–clonic seizures are also common. Additionally, about half of patients will have status epilepticus, usually the nonconvulsive type, which is characterized by dizziness, apathy, and unresponsiveness. The seizures can cause sudden falling (or spasms 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.

Causes

There is no uniform cause: in 20% of those affected, the LGS develops from West syndrome.^[5] The medical history frequently includes infantile spasms or focal and generalized seizures.

The most common type of LGS (70–78%) is symptomatic (secondary) - that is an identifiable underlying pathology is responsible.^[6] This includes encephalopathy (brain damage) or another disease and/or developmental disorder. Frequent causes include tuberous sclerosis, hereditary metabolic diseases, inflammatory brain disease such as encephalitis, meningitis, and toxoplasmosis; hypoxia–ischemia injury and other birth injuries; and lesions of the frontal lobe. These patients tend to have a worse prognosis than those with idiopathic (unknown cause) LGS.^[5]

Progress in genome and exome sequencing is revealing that some individuals diagnosed with Lennox Gastaut Syndrome have de novo mutations in a variety of genes, including CHD2, GABRB3, ALG13 and SCN2A^[7][8] The Epi4K study consortium (2013) observed de novo mutations in at least 15% of a study cohort of 165 patients with LGS and Infantile Spasms using whole exome sequencing.^[9] A 2013 study by Lund and colleagues found a high frequency of rare Copy Number Variants (CNV's) in adult patients with LGS or LGS-like epilepsy^[10]

In up to one-third of cases no cause can be found.^[5]

Lennox–Gastaut syndrome and 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

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

Medication

No high quality evidence has shown any drug very useful as of 2013.^[11] Rufinamide, lamotrigine, topiramate and felbamate may be useful.^[11]

First-line drugs

• Rufinamide^[12]
• valproates (valproic acid, sodium valproate and valproate semisodium)
• felbamate
• benzodiazepines, specifically clonazepam, nitrazepam, and clobazam

Nitrazepam is not approved in the USA.

Clobazam was approved by the FDA on 10/24/11.

Second-line drugs

In 1999, 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 a group of patients taking topiramate experienced a minimum 50% reduction in seizures (specifically drop attacks and tonic–clonics), compared with 8% in the placebo group.^[13] 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.^[14]

Motte reported in 1997 that lamotrigine 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.^[15] Two years later, it was approved by Health Canada for adjunctive therapy in Lennox Gastaut in adults and children.^[16] The United States Food and Drug Administration approved it for that in August 1998.^[17]

Felbamate is indicated in the use of LGS in the event that everything else fails,^[18] and was found to be superior to placebo in controlling treatment resistant partial seizures and atonic seizures.^[19][20] However, it has been known to cause aplastic anemia and liver toxicity.^[21]

Surgical

Palliative surgery reduces the severity and generalization of seizures to the whole brain, but does not influence the seizures sources.

• vagus nerve stimulation
• corpus callosotomy

In eligible symptomatic patients, who can be validated by brain imaging techniques, curative surgery could remove seizures sources. Depending on the source size, surgery will be a resection (removal of small brain areas), disconnection (larger areas) and in somes case hemispherectomy (a full hemisphere disconnection or removal).

In the past, LGS patients were considered de facto as non eligible for epilepsy curative surgery, as scientists were thinking the LGS was a fully generalized epilepsy in all cases. Since around 2010 this assumption has been reviewed and all surgery options, including curative surgery, must be evaluated.^[22] Two studies on LGS patients series who underwent curative surgery in Korea^[23] and China,^[24] showed very good results, up to seizure freedom (Engel class I) for 80% of these patients below 5 years old, and 40% above 5 years old. Nevertheless, like all epilepsy curative surgeries, seizures may recur in the years following surgery, but surgery allows the child to have better brain development during the seizure free period.

Other

Ketogenic diet

A ketogenic diet is a diet that causes ketosis, a state in which there is an increased amount of ketones 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.^[25]

Prognosis

The mortality rate ranges from 3-7% in a mean follow up period of 8.5 to 9.7 years. Death is often related to accidents.^[26]

Epidemiology

LGS is seen in approximately 4% of children with epilepsy, and is more common in males than in females. ^[6] Usual onset is between the ages of three and five.^[3] Children can have no neurological problems prior diagnosis, or have other forms of epilepsy. West syndrome is diagnosed in 20% of patients before it evolves into LGS at about 2 years old.^[5]

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 to 1985.^[27]

United States

0.026% of all children in the Atlanta, Georgia 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 demonstrating slow spike-wave complexes (<2.5 Hz)." The study concluded that LGS accounts for 4% of childhood epilepsies.^[6]

History

LGS was named for neurologists William G. Lennox (Boston, USA) and Henri Gastaut (Marseille, France).

Community

Caregivers of individuals living with Lennox-Gastaut Syndrome may seek support and information from a variety of resources including the LGS Foundation and the Epilepsy Foundation of America. The LGS Foundation offers an international conference every 18 months in the United States, regional support groups, online support groups, and numerous other programs and services.

International LGS Awareness Day is November 1 annually.

Research

Vigabatrin 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).^[28]

Zonisamide showed promise in an overview of controlled and uncontrolled trials conducted in Japan.^[29] However, in a physician survey conducted December 2004, only 28% of Lennox–Gastaut and West syndrome patients improved on zonisamide.^[30]

Medical cannabis or specifically cannabidiol. One yet to be published study from 2017 supported the use of cannabidiol.^[31]

See also

• Epilepsy
• West syndrome
• Ohtahara syndrome
• Syndromes
• Epilepsy Phenome/Genome Project

References