Lennox–Gastaut syndrome

Lennox–Gastaut syndrome
Generalized 2.5 Hz spike and wave discharges in a child with childhood absence epilepsy
Specialty	Neurology

Lennox–Gastaut syndrome (LGS) is a complex, rare, and severe childhood-onset

The symptoms vary and progress with age and are characterized by a triad of seizures including tonic seizure, cognitive dysfunction, and EEG findings. The triad may not fully emerge until 1–2 years after first seizure episode.[1]

Seizures

The peak age of onset of seizures is in the first year of life and the seizures evolve into LGS typically between 3 and 5 years of age.

Tonic seizures are the most common and present in nearly everyone with LGS.^[10][11] They occur most frequently during non-REM sleep (90% of the time). They initially last for a minute or less and are activated by sleep. The presentation can be subtle.^[12] They present often as tonic eyelid opening with some changes in breathing coupled with pupillary dilation, urinary incontinence, increased heart rate, and flushing.^{[citation needed]}

Nonconvulsive status epilepticus occurs in about 50% of patients with LGS. The seizures can cause sudden falling often leading to injury. These "drop attacks" are typically the first manifestation of LGS. The attacks are characterized by a single, generalized myoclonic jerk that precedes tonic contraction of axial muscles.^{[citation needed]}

EEG findings

Findings that strongly suggest LGS include abnormal, consistent slow spike-wave (< 3 hertz [Hz]) on awake EEG. The complexes typically consist of a spike (duration < 70 milliseconds) or a sharp wave (70–200 milliseconds), followed first by a positive deep trough, then a negative wave (350–400 milliseconds). Not every wave is preceded by a spike. Bursts increase and decrease without clear onset and offset. Slow spike waves may occur during seizures or between seizures, or may occur in absence of any observable clinical changes. This helps distinguish LGS from the pattern of extended 3-Hz spike-wave discharges.^{[citation needed]}

Causes

The LGS disease pathophysiology is mostly unknown, but some evidence implicates cortical hyperexcitability occurring at critical periods of brain development.^{[citation needed]}

A lot is known about what causes early life seizures and everyone with LGS has it secondary to a seizure etiology. There are two types of LGS etiologies: idiopathic and secondary. The cause of the idiopathic subtype is unknown. The cause of the secondary subtype occurs when an identifiable underlying pathology is responsible and you can see this pathology on an MRI scan. The most common type of LGS (70–78%) is secondary.^[13] These patients tend to have a worse prognosis than those with idiopathic LGS.^[14] In up to one-third of cases no cause for seizures can be found.^[14]

Brain injury

Seizures that then evolve into LGS most often occur secondary to brain damage. The brain damage can occur from perinatal insults, encephalitis, meningitis, tumor, and brain malformation.^[1]

Genetic mutations

Other identified causes of early life seizures include genetic disorders such as tuberous sclerosis and inherited deficiency of methylene tetrahydrofolate reductase. Some of these cases once thought to be of unknown cause may have definitive etiology by modern genetic testing.^[14]

Progress in

Mutations in the IQSEC2 gene have been associated with this syndrome.^[19] This gene is located on the short arm of the X chromosome (Xp11.22).^{[citation needed]}

While we know a lot about what causes early life seizures, we do not know why some children's seizures evolve into LGS.

Diagnosis

The diagnosis of LGS should be suspected in children less than 8 years old with seizures of multiple types that cannot be treated with anti-seizure medications. Because of high risk of irreversible brain damage in early stages of syndrome (particularly in infants and young children), early diagnosis is essential. Nobody is born with LGS, it evolves over time, so it may take 1–2 years after first initial seizure for all criteria for diagnosis to emerge, so LGS should be considered if there are suggestive signs and symptoms without presence of complete triad.^{[citation needed]}

To confirm diagnosis, awake and asleep EEG and magnetic resonance imaging (MRI) are performed. MRI is used to detect focal brain lesions.^{[citation needed]}

The diagnosis of LGS should also be considered in adults who have childhood-onset, intractable seizures, and intellectual disability.

Ruling out other diagnoses

Certain diagnoses must be ruled out before diagnosing LGS. These diagnoses are:^{[citation needed]}

• Doose syndrome
• Dravet syndrome
• pseudo-Lennox–Gastaut syndrome (atypical benign partial epilepsy)

LGS is more easily distinguished from Doose syndrome by seizure type after the syndrome has progressed. Doose syndrome has more myoclonic seizures and LGS has more tonic seizures. The Doose syndromes is less likely to have cognitive disabilities.^{[citation needed]}

Pseudo-Lennox–Gastaut syndrome can be distinguished from LGS because pseudo-LGS has different spike-and-wave patterns on EEG.^{[citation needed]}

Treatment

There are several treatment options, including medications, surgery, and diet.

Medications

In most patients with LGS, the treatment does not end seizure recurrence.

The goals of treatment are to lower frequency and severity of seizures to greatest extent possible. There are no studies using only one medication. Lamotrigine and rufinamide used as add-ons are very effective in reducing overall seizures, but do not stop them.^[20]

The treatments for LGS has evolved over the years. Various treatments have been shown to have some degree of efficacy. In 1997–1999, lamotrigine was found to be effective and approved by the Food and Drug Administration and Health Canada.^[21][22][23] In 1999, topiramate trials showed that topiramate decreased seizure occurrence by more than 50%.^[24][25]

• valproate (
  valproate semisodium)^{[citation needed}
  ]

• lamotrigine^[30]

Third-line drugs

• rufinamide^[30]
• topiramate^[30]
• clobazam ^[30]
• felbamate^[30]
• cannabidiol ^[31]

Adjuvant drugs

Are the following:^{[citation needed]}

• benzodiazepines: clonazepam, nitrazepam
• zonisamide

Surgery

In the past, LGS patients were not eligible for surgery, as the medical community thought it to involve the whole brain as a generalized epilepsy in all cases. Since 2010, this assumption has been challenged.^[32] Two studies on LGS patients series who underwent curative surgery in Korea^[33] and China,^[34] showed very good results, up to seizure freedom for 80% of these patients below 5 years old, and 40% above 5 years old. 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.^{[citation needed]}

There are several procedures that have shown efficacy:^{[citation needed]}

• vagus nerve stimulation, which involves implantation of battery-operated generator of intermittent electrical stimuli to an electrode wrapped around left vagus nerve. Some studies have been shown it to have greater than 50% reduction in seizures reported in more than half of patients.
• corpus callosotomy, which has shown to be effective with atonic seizures. This procedure is considered in cases in which vagus nerve stimulation has failed
• transcranial direct current stimulation
• resection

Diet

A ketogenic diet is a diet that causes ketosis, a state in which there is an increased amount of ketones in the body. Adopting and maintaining rigid diet may be difficult for some families. Short-term ketogenic diet might be associated with nonsignificant decreases in frequency of parent-reported seizures in children with LGS.^[35] A case series study showed 50% seizure reduction reported in almost half of children with LGS after 1 year of ketogenic diet. However, the strength of the study is challenged because it represents reports rather than scientific analysis of the clinical outcomes such as in a randomized controlled trial.^[36]

Prognosis

The mortality rate ranges 3–7% in a mean follow up period of 8.5 to 9.7 years. Death is often related to accidents.^[37]

Epidemiology

LGS is seen in approximately 4% of children with epilepsy, and is more common in males than in females.

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.^[38]

United States

0.026% of all children in the

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).^[39]

Soticlestat is an investigational anticonvulsant that was well tolerated and reduced seizure frequency in a phase 2 clinical study for the treatment of Lennox-Gastaut syndrome^[42][43][44] and began phase 3 trials in 2022.^[44]

Lennox-Gastaut Syndrome Foundation

The Lennox-Gastaut Syndrome (LGS) Foundation, based in