Lennox-Gastaut Syndrome (LGS)

Lennox-Gastaut syndrome (LGS) is a severe, disabling form of epilepsy characterized by frequent drug-resistant seizures, impaired cognition, and slow spike-and-wave patterns on electroencephalography (EEG). LGS typically manifests in children between 2 and 5 years of age, but as recurrent seizures persist into adulthood, the disease causes many patients to suffer progressive injury, impairment, and debilitation.¹ 

Classification of LGS

LGS is classified as either secondary (symptomatic) or idiopathic (cryptogenic).²

Most children (75%) with LGS have the secondary form, in which their disease can be linked to an underlying pathology of diffuse cerebral injury. Causes include tuberous sclerosis, infectious or inflammatory conditions such as encephalitis and meningitis, birth injury or trauma, hypoxic-ischemic insult, metabolic disorders, and developmental brain malformations. Approximately 30% of children in whom LGS develops have a previous history of West syndrome or infantile spasms.³ 

In 25% of cases, LGS is idiopathic, with no known cause. The onset is later in these cases. Genetic research has shown de novo mutations in a variety of genes, including SCN1A, GABRB3, ALG13, and CHD2, in patients with idiopathic LGS. At present, it is unclear whether these mutations actually contribute to the emergence of LGS.³

The EEG findings are similar in patients with genetic, lesional, or unidentified causes of LGS, pointing to a common underlying mechanism.¹

Read more about LGS genetics

Pathophysiology of LGS

The pathophysiology of LGS is unknown, and no single pathophysiologic feature drives its development. Animal models are nonexistent. Age-dependent expression suggests that the immature brain is prone to formation of the LGS phenotype.^1,4 Among the proposed possible pathophysiologic mechanisms, one theory states that as the anterior regions of the brain mature, excessive permeability develops in the excitatory interhemispheric pathways in the frontal lobes.⁴ 

Possible Role of Structural Abnormalities

In approximately 10% to 30% of individuals, an epileptogenic abnormality may be seen on structural magnetic resonance imaging (MRI); these abnormalities may be focal, multifocal, or diffuse and include encephalitis, focal cortical dysplasia, ischemic stroke, perinatal anoxia, and intracranial hemorrhage.¹ 

An altered structure of the brain is the most common cause of LGS symptoms. Infection during pregnancy and genetic mutations are other causes. Various mechanisms of brain injury in early life can cause LGS, including poor blood flow or oxygen levels in the brain (hypoxic-ischemic encephalopathy), early radiation to the brain, infection of the brain (encephalitis, meningitis), and stroke.⁵ 

However, it is significant that the electroclinical characteristics of tonic seizures and interictal discharges in LGS are notably similar whether or not a causative lesion can be identified, and independent of lesion location or pathologic features. There seem to be unknown factors that determine whether an individual will express with LGS.¹ 

Read more about LGS etiology

Possible Role of Immunogenetic Mechanisms

It is also believed that immunogenetic mechanisms contribute to the development or persistence of disease in some cases of LGS. Although one research study identified a strong association between LGS and human lymphocyte antigen class I antigen B7, another study could not find any such association. No distinct or homogeneous metabolic patterns were found in 2 separate reports of positron emission tomography (PET) studies in children with LGS.⁴  

On the basis of clinical and neurophysiological data, it has been determined that LGS is an epileptic reticulo-thalamo-cortical system disorder characterized by self-sustained epileptogenicity, in which the reticular system between the midbrain and the thalamus becomes epileptogenic and activated. In addition, it is believed that the reticular formation is the major neural substrate generating symptomatic generalized epilepsy.⁶ 

Read more about LGS diagnosis

References

1. Archer JS, Warren AE, Jackson GD, Abbott DF. Conceptualizing Lennox-Gastaut syndrome as a secondary network epilepsy. Front Neurol. 2014;5:225. doi:10.3389/fneur.2014.00225
2. Camfield PR. Definition and natural history of Lennox-Gastaut syndrome. Epilepsia. 2011;52 Suppl 5:3-9. doi:10.1111/j.1528-1167.2011.03177.x
3. Amrutkar C, Riel-Romero RM. Lennox Gastaut syndrome. StatPearls [Internet]. Updated August 1, 2022. Accessed March 4, 2023.
4. Cherian KA. Lennox-Gastaut syndrome. Medscape. Updated August 6, 2020. Accessed March 4, 2023.
5. What causes LGS? LGS Foundation. Accessed March 4, 2023.
6. Yagi K. The pathophysiology of Lennox-Gastaut syndrome–a review of clinico-electrophysiological studies. J Epileptol. 2015;23(1):7.

Reviewed by Kyle Habet, MD, on 3/27/2023.

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Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.