Lennox-Gastaut Syndrome (LGS)

Lennox-Gastaut syndrome (LGS) is a rare, severe epileptic encephalopathy of childhood characterized by multiple seizure types, specific brain wave patterns on electroencephalography, and cognitive impairment.¹ 

The onset of a patient’s seizures is usually during the first decade of life and most commonly in children approximately 3 to 5 years of age. Although it happens very rarely, it is possible for the onset of LGS to be in late childhood or even adolescence.^2-4

The etiology of most cases of LGS can be linked to various factors, but approximately 25% of cases have no identifiable cause. Therefore, LGS is subdivided into 2 etiological categories: secondary (symptomatic) LGS and idiopathic (cryptogenic) LGS.¹

Etiology of Secondary (Symptomatic) LGS

In secondary LGS, which accounts for approximately 75% of cases, an underlying pathology is identified as the causative factor.¹ This may be structural, genetic, metabolic, immunological, or infectious in nature. Also, some cases of secondary LGS are rooted in other types of childhood epilepsy, which then evolve into LGS.^2,5

Structural Causes

The most common cause of LGS is an alteration in the structure of a patient’s brain. Such abnormalities can be visualized on magnetic resonance imaging (MRI). Computed tomography (CT) may be preferred in acute situations, such as when a patient sustains head trauma during a seizure episode.^5,6 

The structural causes of LGS are subdivided into 2 groups: congenital brain malformations and acquired brain injuries.^2,5

Read more about LGS diagnosis

Congenital Brain Malformations

Congenital brain malformations develop while a fetus is in utero. Often, the cause of a congenital brain malformation is unknown. Experts speculate that a genetic abnormality may affect fetal development; other possible causes are infection during early pregnancy and fetal injury during pregnancy.^2,5

Although LGS is usually caused by diffuse, bilateral encephalopathy, it is also possible for a localized brain lesion, such as focal cortical dysplasia, to cause LGS.⁷ Cortical dysplasia, which results from abnormal cortical development, is a congenital condition that frequently causes refractory epilepsy, as in children with LGS.⁸

Acquired Brain Injuries

An acquired brain injury is one that occurred either during delivery or very early in life after normal development of the brain in utero.^2,5 Such injuries may include or be caused by situations such as: 

• Lack of oxygen or blood flow to the brain (hypoxic-ischemic encephalopathy [HIE])
• Stroke, injury during birth, frontal lobe injury, and bleeding or inflammation in the brain
• Brain infections such as meningitis and encephalitis
• Early radiation to the brain^2,5 

Genetic Causes

Genetic disorders are being increasingly recognized as a cause of early-onset epileptic conditions such as LGS.² Genetic abnormalities can influence how the brain develops in utero. Some may be acquired “de novo,” meaning they are new and not present in other family members.²

Genetic abnormalities may result in structural changes to the brain, including tuberous sclerosis complex and other conditions visible on MRI.^2,5 Sometimes, genetic abnormalities may cause microscopic changes that cannot be detected on neuroimaging.^2,5

Genetic testing, including whole-exome sequencing and epilepsy panel testing, can reveal genetic causes in up to 40% of children with unexplained LGS.^5,9 Families should receive genetic counseling before and after genetic testing because the results may be relevant for immediate family members.⁵

Read more about LGS genetics 

Metabolic Causes

Although metabolic disorders rarely cause LGS, they are a possible explanation for the development of the condition.^1,2,5 

Metabolic disorders are typically caused by an abnormal breakdown of specific nutrients in the body. As a result, toxins accumulate and cannot be removed efficiently. A metabolic disorder can cause brain damage if important nutrients that nourish brain cells are lacking or if toxins build up within brain tissue that lead to brain dysfunction and inflammation.⁵

Some metabolic disorders can be diagnosed with blood, urine, or cerebrospinal fluid testing; others may be diagnosed via genetic testing.⁵ 

Read more about LGS testing

Immunological Causes

Abnormal immune responses can cause aberrant antibodies or proteins to form that may injure or damage the brain and lead to the development of LGS. An immunological response may be considered when the onset of seizures is soon after an infection or vaccination. Immunological responses and their effect on the central nervous system can be confirmed with blood and spinal fluid testing.⁵

Infectious Causes

Although rare, infections that occur prenatally or during early childhood can cause brain inflammation and injury, leading to LGS.⁵

Progression of Other Childhood Epileptic Syndromes

Approximately 30% of children with LGS have a history of other types of childhood epilepsy, including West syndrome, Ohtahara syndrome, and infantile spasms, which progress and evolve to LGS.^1,10

Etiology of Idiopathic (Cryptogenic) LGS

In approximately 25% of cases of LGS, no underlying pathological explanation can be identified. Often, the onset of seizures is later in these cases.¹

Some unexplained cases may be due to undiscovered genetic causes. The recent identification of specific de novo mutations in certain genes, including SCN1A, GABRB3, ALG13, and CHD2, may provide some explanation for the development of idiopathic (cryptogenic) LGS. However, the way these genetic variations relate to the pathogenesis of LGS is currently unknown.¹

Read more about LGS pathophysiology

References

1. Amrutkar C, Riel-Romero RM. Lennox Gastaut syndrome. StatPearls [Internet]. Updated August 1, 2022. Accessed February 28, 2023. 
2. Lennox-Gastaut syndrome LGS. Epilepsy Foundation. Accessed February 28, 2023.
3. Asadi-Pooya AA, Farazdaghi M. Age at onset in patients with Lennox-Gastaut syndrome: correlations with clinical manifestations. J Clin Neurosci. 2022;100:138-142. doi:10.1016/j.jocn.2022.04.020
4. Al-Banji MH, Zahr DK, Jan MM. Lennox-Gastaut syndrome. Neurosciences (Riyadh). 2015;20(3):207-212. doi:10.17712/nsj.2015.3.20140677
5. What causes LGS? LGS Foundation. Accessed February 28, 2023.
6. Cherian KA. Lennox-Gastaut syndrome workup: neuroimaging studies. Medscape. Updated August 6, 2020. Accessed February 28, 2023.
7. Liu SY, An N, Fang X, et al. Surgical treatment of patients with Lennox-Gastaut syndrome phenotype. Sci World J. 2012;2012:e614263. doi:10.1100/2012/614263
8. Kabat J, Król P. Focal cortical dysplasia – review. Pol J Radiol. 2012;77(2):35-43. doi.10.12659/pjr.882968
9. Lennox-Gastaut syndrome. Children’s Hospital of Philadelphia. Accessed February 28, 2023.
10. Ohtahara syndrome. Epilepsy Foundation. Accessed February 28, 2023.

Reviewed by Kyle Habet, MD, on 3/30/2023.

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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.