Lennox-Gastaut Syndrome (LGS)

Lennox-Gastaut syndrome (LGS) is a rare, severe, epileptic condition, often manifesting in children between the ages of 2 and 5 years. It is characterized by a triad of criteria, including episodes of multiple types of seizures, a specific brain wave pattern called the slow spike-and-wave pattern as seen on electroencephalogram (EEG), and varying degrees of cognitive impairment.¹ 

Recent studies have worked to identify the causation of the two types of LGS: symptomatic and idiopathic. Identifiable causes and risk factors are linked to the symptomatic form of LGS, which affects 65% to 75% of individuals with the disease. These risks and causes include brain injury, structural abnormalities, or other epileptic encephalopathic conditions. The remaining 25% to 35% of individuals with LGS have idiopathic or cryptogenic LGS. Many studies have linked genetic de novo mutations to LGS, suggesting a possible role in causation or risk.²  

Brain Injury or Structural Abnormalities

Babies who develop brain malformations and abnormalities while in utero, those who have structural abnormalities leading to obstruction of circulation to the brain, and babies who sustain a brain injury during delivery are more predisposed to develop LGS.³ Children who experience brain injuries, including tumors, strokes, or hypoxia, during early childhood also may develop LGS.⁴

Children who have experienced infections of the brain or any neurological condition, particularly cortical dysplasia, in which the brain fails to develop necessary neural connections during development in utero, also demonstrate an increased risk for LGS. Cortical dysplasia is one of the biggest risk factors for LGS.³

Read more about LGS comorbidities

Studies Related to LGS Risk From Structural Abnormality or Injury

Focal cortical dysplasia, in addition to increasing the risk of epilepsy, also correlates with cognitive impairment. According to one study, earlier age at seizure onset, as well as the magnitude of the area of the brain affected by the cortical dysplasia lesion (widespread dysplastic involvement) both correlate with cognitive performance testing scores and intelligence quotient (IQ) variance.⁵

Another study identified that the most common risk factors for epileptic encephalopathies, including LGS, were premature birth, severe asphyxia, placenta disorders, hyperbilirubinemia, sepsis, and periventricular leukomalacia. The presence of any of these factors at birth suggests the need for continued neonatal follow-up to identify and promptly treat epileptic encephalopathies such as LGS. ⁶

Read more about LGS diagnosis

Evolution to LGS From Other Epileptic Syndromes

LGS tends to evolve from other epileptic encephalopathic conditions, including West syndrome, Ohtahara syndrome, and tuberous sclerosis complex. Children diagnosed with these types of epileptic conditions or those who experience infantile spasms are at risk of evolution to LGS.⁴ 

A 2009 study by You et al. discovered that children with West syndrome placed on a ketogenic diet had a significantly reduced risk for evolution to LGS. A group of children with West syndrome being treated with prednisolone, adrenocorticotropic hormone, or a combination of these two therapies, demonstrated a similarly reduced risk for evolution. Therefore, hormone therapy and a ketogenic diet may be crucial treatment factors that alter the risk of progression to LGS.⁷

Additionally, individuals with a history of experiencing multiple seizure types are more at risk of being diagnosed with LGS, given that this is one of the three essential criteria for diagnosis of LGS.⁴

Read more about LGS clinical features

Treatment-Resistant Seizures

Children who experience early-in-life seizures that prove resistant to antiseizure medication (ASM) treatment are more at risk of developing LGS. Failure of more than 2 ASMs also increases the risk of LGS.⁴

Read more about LGS treatment

Tuberous sclerosis complex can progress to LGS. Researchers assessed risk factors in 83 patients with tuberous sclerosis complex that were associated with treatment resistance seizures and severe cognitive impairment, as seen in LGS.⁸ The risk factors that were associated with treatment resistance included⁸:

• History of seizures in the neonatal period
• Onset of seizures prior to age 2 years
• Progression of tuberous sclerosis complex to LGS
• More than 3 tubers identified on neuroimaging
• Generalization of electroencephalogram (EEG) results
• Presence of infantile spasms
• Autism
• Diagnosis of status epilepticus

In addition to these 8 risk factors for treatment resistance, 2 other risk factors associated with severe cognitive impairment include the presence of subependymal giant cell astrocytoma (SEGA) on neuroimaging and a history of treatment with more than 3 antiseizure medications.⁸

Genetics

Approximately 3% to 30% of individuals with LGS report a family history of epilepsy, suggesting the role of possible genetic factors in LGS etiology.¹ Children with genetic mutations in any of the 150 plus genes that have been identified as related to epilepsy are at increased risk for developing LGS.⁴ These genetic mutations can occur in unidentified genes as well, offering potential explanations for cases of LGS with unknown etiology. Possible genetic mutations predisposing children to development of LGS include TSC1, SCN2A, SCN1A, CDKL5, Dup15q, and Trisomy 21.⁴

Read more about LGS genetics

References

1. Lennox-Gastaut syndrome. Medline Plus. Accessed February 9, 2023.
2. Jahngir MU, Ahmad MQ, Jahangir M. Lennox-Gastaut syndrome: in a nutshell. Cureus. 10(8):e3134. doi:10.7759/cureus.3134
3. Lennox-Gastaut syndrome. Sonas Home Health Care. Accessed February 9, 2023.
4. What causes LGS? LGS Foundation. Accessed February 9, 2023.
5. Allone C, Bonanno L, Lo Buono V, et al. Neuropsychological assessment and clinical evaluation in temporal lobe epilepsy with associated cortical dysplasia. J Clin Neurosci. 2020;72:146-150. doi:10.1016/j.jocn.2019.12.041
6. Ricardo-Garcell J, Harmony T, Porras-Kattz E, et al. Epileptic encephalopathy in children with risk factors for brain damage. Epilepsy Res Treat. 2012;2012:747565. doi:10.1155/2012/747565
7. You SJ, Kim HD, Kang HC. Factors influencing the evolution of West syndrome to Lennox-Gastaut syndrome. Pediatric Neurology. 2009;41(2):111-113. doi:10.1016/j.pediatrneurol.2009.03.006
8. Gül Mert G, Altunbaşak Ş, Hergüner Ö, et al. Factors affecting epilepsy prognosis in patients with tuberous sclerosis. Childs Nerv Syst. 2019;35(3):463-468. doi:10.1007/s00381-019-04066-7

Reviewed by Hasan Avcu, MD, on 3/28/2023.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.