Lennox-Gastaut Syndrome (LGS)

Lennox-Gastaut syndrome (LGS) is a rare, severe type of childhood epilepsy identified by Dr. Henri Gastaut in Marseille, France, in 1966. However, the electroencephalographic (EEG) aspects of the disorder were first described by Dr. William G. Lennox of Boston, Massachusetts in 1950. Thus, this eponymous syndrome carries the names of these 2 neurologists. LGS is characterized by compounded variable seizure types, distinctive EEG abnormalities, and intellectual disability.¹

Epidemiology of LGS

The estimated incidence of LGS is 0.1 to 0.28 per 100,000 population.¹ LGS is more likely to develop in boys than in girls. The prevalence is 0.1 cases per 1000 population for boys vs 0.02 cases per 1000 population for girls (relative risk, 5.31).² The mean age of children at the onset of epilepsy is 26 to 28 months, with a range of 1 day to 14 years.²

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Etiology and Classification of LGS

The 2 recognized forms of LGS are based on etiology: secondary or symptomatic LGS and idiopathic or cryptogenic LGS. Most children (75%) with LGS have the secondary form, resulting from an underlying structural abnormality of the brain. Causes include tuberous sclerosis; infectious or inflammatory conditions such as encephalitis and meningitis; birth injury or trauma; hypoxic-ischemic insult; metabolic disorders; and developmental cortical malformations. Approximately 30% of children in whom LGS develops have a previous history of West syndrome or infantile spasms.^1,3

In 25% of cases, LGS has no known cause (cryptogenic). The onset of disease is later in these cases. Genetic research has shown de novo mutations in a variety of genes, including SCN1A, GABRB3, ALG13, and CHD2. Up to 30% of families with affected children have a family history of epilepsy.^1,3 

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Signs and Symptoms of LGS

LGS presents with a variety of seizures types, including tonic, generalized tonic-clonic (grand mal), atonic, atypical absence, and myoclonic seizures.^3,4 

The symptoms of a tonic seizure include increased muscle stiffness and tone. The seizures are usually brief, lasting from a few seconds to a minute, with loss of consciousness. Tonic seizures are more frequent at night during sleep but may also occur during the day.^5,6

The symptoms of atonic seizures, also called drop attacks, include the sudden loss of muscle tone and limpness. Atonic seizures can cause head nod, postural difficulties, and sudden falls. They usually last for a few seconds and partially affect consciousness.^5,6 

Unlike typical absence seizures, the atypical absence seizures found in LGS involve more than episodes of staring. They may also cause involuntary responses, such as chewing movements, lip smacking or jerking, or eye blinking ¹ 

Delayed developmental milestones, behavioral problems, and cognitive dysfunction are frequent in patients with LGS.^5,6

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Diagnosis of LGS

In addition to recognizing the symptoms of LGS, physicians use a variety of methods to diagnose LGS, including EEG and neuroimaging studies, an evaluation of the patient’s family and birth history, and the patient’s developmental, cognitive, and genetic/metabolic status.⁷ 

Characteristic EEG findings include slow background rhythm and slow (<3 Hz) spike wave discharges, which may not be present at the onset of a seizure.³ Regular monitoring and several EEG studies are required before the diagnosis can be confirmed.¹

Computed tomography and magnetic resonance imaging may be used to detect the type and location of abnormalities within the brain.⁵

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Treatment of LGS

The treatment of LGS is focused on seizure control, which is attempted with pharmaceutical therapies, dietary interventions, and surgical management. Seizure control improves alertness, mood, cognition, and overall quality of life.¹ 

Patients may present with various types of seizures, and these types and frequency of seizures can change over disease progression. Treatment should be prioritized for certain seizure types, such as tonic and atonic seizures, as they are associated with falls and accidents. Seizures may also be refractory to treatment and need multiple medications.¹  

Depakote® (valproate) is often the first-line medication for many types of seizures associated with LGS. Clobazam (sold as Onfi® and Sympazan™), Felbatol® (felbamate), Lamictal® (lamotrigine), Banzel® (rufinamide), Topamax® (topiramate), and Epidiolex® (cannabidiol) are a few additional antiseizure medications.⁸

Other approaches to treatment include corpus callosotomy, vagus nerve stimulation, and dietary therapy (ketogenic diet). To improve seizure control, medications may be administered together with other treatments.⁸

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Prognosis of LGS

The overall prognosis for children with LGS is variable and unfavorable.² Antiseizure medications are often not effective for the treatment of LGS seizures, as a medication may help control one type of seizure but worsen another type. It is crucial to address the psychosocial needs and behavioral problems of patients with LGS early and consistently.⁹

During 8 to 10 years of follow-up, the mortality rate ranges from 3% to 7%. Accidents in seizures are a high risk of death. The Sudden Unexpected Death in Epilepsy (SUDEP) rate is also higher in patients with LGS, as seizures are often uncontrolled. The prognosis is typically poorer for patients with secondary LGS than idiopathic LGS, also due to uncontrolled seizures.¹

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References

1. Amrutkar C, Riel-Romero RM. Lennox-Gastaut syndrome. StatPearls [Internet]. Updated August 1, 2022. Accessed February 12, 2023.
2. Cherlan KA. Lennox-Gastaut syndrome. Medscape. Updated August 6, 2020. Accessed February 12, 2023. 
3. Al-Banji MH, Zahr DK, Jan MM. Lennox-Gastaut syndrome. Management update. Neurosciences (Riyadh). 2015;20(3):207-212. doi:10.17712/nsj.2015.3.20140677
4. Lennox-Gastaut syndrome. Children’s Hospital of Philadelphia. Accessed February 12, 2023.
5. Lennox-Gastaut syndrome. Cedars-Sinai. Accessed February 12, 2023.
6. Lennox-Gastaut syndrome. NORD – National Organization for Rare Disorders. Updated June 5, 2020. Accessed February 12, 2023. 
7. Resnick T, Sheth RD. Early diagnosis and treatment of Lennox-Gastaut syndrome. J Child Neurol. 2017;32(11):947-955. doi:10.1177/0883073817714394
8. Lennox-Gastaut syndrome. National Institute of Neurological Disorders and Stroke (NINDS). Accessed February 12, 2023.
9. Lennox-Gastaut syndrome LGS. Epilepsy Foundation. Accessed February 12, 2023. 

Reviewed by Debjyoti Talukdar, MD, on 2/27/2023.

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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.