Lennox-Gastaut Syndrome: Pediatric Primary Care Guide

Guidance for primary care clinicians diagnosing and managing children with Lennox-Gastaut syndrome

Abstract: Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy (DEE), which commonly begins in early childhood and is characterized by frequent seizures of multiple different types, particularly tonic (stiffening) and atonic (drop) seizures, neurodevelopmental delays, and characteristic electroencephalogram (EEG) abnormalities. LGS may evolve from other epilepsy syndromes, most commonly from infantile spasms¹.

Keywords: Antiseizure medication (ASM), aspiration pneumonia, atonic (drop) seizures, corpus callosotomy, developmental delay, electroencephalogram (EEG), epileptic encephalopathy, genetic testing, ketogenic diet, Lennox-Gastaut syndrome (LGS), mobility impairment, neurostimulation devices, pediatric neurology, tonic seizures

Key Points

Seizures and safety
There is an increased risk of injury from falls during seizures, especially atonic (drop) seizures. Many individuals with LGS may benefit from a seizure helmet for head protection.

Sudden unexpected death in epilepsy
There is an increased risk of sudden unexpected death in epilepsy (SUDEP). Adherence to antiseizure medications (ASMs) is essential for decreasing the risk of SUDEP, and the use of seizure alert devices may be beneficial.

Aspiration pneumonia
Aspiration pneumonia may result from unintentional inhalation of saliva during a seizure. This risk can be enhanced in individuals taking medications that cause excess salivation and/or sedation.

Mobility and impairment
Individuals with LGS often have challenges with balance, muscle coordination, and mobility, which can include dysphagia (difficulty swallowing). Assistive mobility (walker, wheelchair) and eating devices (feeding tube, gastrostomy tube) may be indicated in some individuals.

Early screening
Developmental delay and learning and behavior problems are common. Early developmental screening and referral to developmental therapies are essential for pediatric patients with this syndrome.

Early treatment
Treatment of epilepsy with antiseizure medications (ASMs) is the mainstay of LGS management. Seizures are typically refractory to multiple medications, and non-pharmacological interventions, including diet therapy, neurostimulation devices, and/or epilepsy surgery, may be indicated.

Early referral to pediatric neurology
Children with LGS should typically be under the care of a pediatric neurologist with expertise in seizures. If possible, a pediatric epileptologist is preferred. If LGS is suspected by a primary care provider, early referral to a pediatric neurologist is highly recommended.

Guidelines

Cross JH, Auvin S, Falip M, Striano P, Arzimanoglou A. Expert Opinion on the Management of Lennox-Gastaut Syndrome: Treatment Algorithms and Practical Considerations. Front Neurol. 2017;8:505. doi:10.3389/fneur.2017.00505²

Auvin S, Arzimanoglou A, Falip M, Striano P, Cross JH. Refining management strategies for Lennox-Gastaut syndrome: Updated algorithms and practical approaches. Epilepsia Open. 2025;10(1):85-106. doi:10.1002/epi4.13075³

Diagnosis

LGS usually appears in preschool-aged children. It typically takes time for all of its features to emerge, making it challenging to accurately diagnose this syndrome in children under 3 years of age.

The diagnosis of LGS is based on a triad of clinical features¹: 

• Multiple seizure types with seizure onset in early childhood
• Characteristic EEG abnormalities
• Developmental delay, intellectual disability

Presentations

The age of onset varies, with the peak occurring between 3-5 years. Approximately 30-50% of individuals have a history of other epilepsy syndrome, most commonly infantile epileptic spasms syndrome². 

Multiple seizure types are present, which can emerge at different ages. The most common to least common are: 

• Tonic seizures – body stiffening, often occur during sleep
• Atypical absence seizures – staring, can have eyelid fluttering, chewing movements, longer duration than typical absence seizures
• Atonic seizures – “drop” seizures, cause sudden loss of body tone, often result in falls
• Myoclonic seizures – rapid jerking movements of one or more extremities, head/shoulders, can occur in isolation or clusters
• Generalized tonic-clonic seizures – “convulsive” seizure, full body stiffening followed by rhythmic non-suppressible jerking movements, can be associated with irregular breathing, apnea, cyanosis
• Focal seizures – can have variable presentation, eye/head deviation in 1 direction, 1 extremity and/or 1 side of body stiff, shaking, or both. Can have normal or impaired awareness

Developmental delays are common, but development is highly variable, and early developmental milestones may be age-appropriate. Close monitoring of developmental progress is essential to ensure developmental therapies are expedited.

Diagnostic Criteria and Classifications

LGS diagnosis is characterized by a triad of clinical features^1,5 : 

1. Multiple seizure types with seizure onset prior to 18 years, often occurring in early childhood
   • Onset of seizures peaks between 3-5 years of age and can evolve from different epilepsy syndromes, such as infantile epileptic spasms syndrome.
   • Primary seizure types include tonic (primarily occurring at night), atonic and atypical absence. Other seizure types may include generalized-tonic clonic, myoclonic, and focal impaired awareness.
2. Abnormal EEG findings
   • Characteristic interictal (in between seizures) diffuse slow spike-wave complexes ≤2.5 hz.
   • Additional EEG features may include generalized paroxysmal fast activity (GPFA) during non-REM sleep.
3. Developmental delay, intellectual disability
   • These features may not necessarily be present at seizure onset and may develop over time.

Diagnostic Testing and Screening

Labs

No specific lab test is diagnostic for LGS. However, labs may help assess for potential etiologies (e.g., metabolic, infectious, or genetic disorders).

Lab monitoring may be indicated in patients taking specific antiseizure medications (i.e., valproic acid, cannabidiol, felbamate) to assess blood cell counts and liver function and ensure medication levels are within therapeutic range.

Imaging

• Electroencephalogram (EEG) study that captures wakefulness and sleep
  • Slow spike-wave complexes ≤2.5hz
  • Generalized paroxysmal fast activity (GPFA) during non-REM sleep
• Magnetic resonance imaging (MRI) – to assess for underlying structural abnormalities (cortical malformations, tumor, stigmata of certain disorders, such as tuberous sclerosis complex)

Genetic Testing

Emerging advances in next-generation sequencing have discovered LGS may be a heterogeneous genetic disorder⁶. 

Genetic testing options include a targeted multigene epilepsy panel, whole exome sequencing, or whole genome sequencing. Early genetic testing should be considered in patients with LGS of unknown etiology.

Testing for Family Members

If a genetic cause of LGS is identified, testing parents may be indicated to determine if the genetic variant was inherited or arose spontaneously (de novo), as this may help inform seizure risk for family members and future family planning.

Genetics

Many genes have been implicated in LGS, including ARX, ALG13, CHD2, DNM1, GABRB3, 
STXBP1, SCN2A, and many others⁶. In most cases, genetic mutations occurred spontaneously (de novo) and were not inherited.

Incidence and Prevalence

Lennox-Gastaut syndrome accounts for approximately 1-2% of individuals with epilepsy and 2-5% of all childhood epilepsies^7,8. The global prevalence of LGS is approximately 5.8 – 60.8 per 100,000.

Differential Diagnosis

• Epilepsy with myoclonic-atonic seizures (EMAS) – also known as Doose syndrome
  • The predominant seizure types include myoclonic and atonic seizures. Tonic seizures are rare, which is a key feature that distinguishes this syndrome from LGS.
• Severe myoclonic epilepsy of infancy (SMEI) – also known as Dravet syndrome
  • Age of seizure onset is earlier than LGS, often <1 year of age
  • Temperature-sensitive/febrile seizures are a characteristic feature. Seizures are often prolonged (status epilepticus) and involve one side of the body (hemiclonic).
  • The majority of patients with Dravet syndrome have a mutation in the SCN1A gene, which impacts sodium channel function in the brain.
• Infantile epileptic spasms syndrome (IESS) – also known as West syndrome
  • Infantile spasms are clusters of sudden, repeated, uncontrolled movements that resemble body crunching, head bobbing, and/or exaggerated startle.
  • Onset peaks between 4-9 months of age but can occur anytime between 2-12 months of age.
  • The characteristic brain wave pattern is called hypsarrhythmia.
  • Many, but not all, individuals with infantile spasms will develop other seizure types, including LGS.

Co-occurring Conditions

Etiology for LGS is identified in approximately 2/3 of cases, with causes including hypoxic-ischemic brain injury, congenital brain malformations, central nervous system infections, tuberous sclerosis complex (TSC), metabolic disease, and genetic causes¹. Approximately 1/3 of children will have no identifiable cause. Genetic causes likely account for most unidentified cases.

Comorbid conditions include intellectual disability and global developmental delay, sleep disturbance, and behavioral disorders such as anxiety disorder, attention deficit hyperactivity disorder, and autism spectrum disorder. 

Prognosis

LGS is a lifelong neurodevelopmental disorder with epilepsy that is often medication-resistant and requires multiple antiseizure medications. Individuals with LGS often live until their adult years but typically cannot live independently and require assistance with activities of daily living. Individuals with LGS can have varying degrees of intellectual and behavioral disabilities, which often range on the severe end of the spectrum. People with LGS have an increased risk of death compared to the general population primarily due to safety risks of uncontrolled seizures, including falls, aspiration pneumonia, and SUDEP.

Treatment and Management

Neurology

Children with LGS will typically be under the care of a pediatric neurologist with expertise in seizures. If possible, a pediatric epileptologist is preferred. There is no cure for LGS, and no universal disease-modifying therapies are currently available. The primary management goal is to reduce or eliminate seizures and mitigate the risk of injury from seizures when able. If LGS is suspected by a primary care provider, early referral to a pediatric neurologist is highly recommended.

Antiseizure Medications

Multiple antiseizure medications (ASMs) are often needed due to the medication-resistant nature of epilepsy in LGS. Patient ASMs should be reviewed regularly to assess potential interactions and perform monitoring labs as recommended. A custom seizure action plan outlining when to administer seizure rescue medication should be addressed and updated annually^9,10. 

There are a number of FDA-approved ASMs specifically for the treatment of LGS. Most individuals will require multiple ASMs as well as non-pharmacologic epilepsy treatments during their lifespan. Valproic acid (Depakote) is considered the first-line treatment for seizures in patients with LGS.

Additional FDA-approved ASMs for adjunct treatment for LGS include:

• Cannabidiol (Epidiolex)
• Clobazam (Onfi)
• Clonazepam (Klonopin)
• Felbamate (Felbatol)
• Fenfluramine (Fintepla)
• Lamotrigine (Lamictal)
• Rufinamide (Banzel)
• Topiramate (Topamax)

Although commonly used, the following agents are not FDA-approved for LGS:

• Levetiracetam (Keppra)
• Brivaracetam (Briviact)
• Zonisamide (Zonegran)
• Lacosamide (Vimpat)
• Ethosuximide (Zarontin)
• Perampanel (Fycompa)

Non-Pharmacological

Non-pharmacological treatment options for medication-resistant epilepsy, which is defined as failure to achieve sustained seizure freedom after adequate trials of 2 tolerated and appropriately chosen antiseizure medications, are often indicated¹¹. 

• Diet therapy
  • Ketogenic diet
  • Modified Atkins diet
• Neurostimulation devices¹²
  • Vagus nerve stimulation (VNS)
  • Deep brain stimulation (DBS)
  • Responsive neurostimulation (RNS)
    • Implantable closed-loop neurostimulation device with electrodes targeting the bilateral centromedian nucleus of the thalamus
• Palliative surgical intervention¹² 
  • Corpus callosotomy to disconnect the 2 hemispheres of the brain can be specifically beneficial for treatment of atonic seizures
  • Resective surgery if there is a lesion or abnormality of concern identified on brain imaging

Declaration of Conflicting Interests

The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author received no financial support for the research, authorship, and/or publication of this article.

References

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3. Auvin S, Arzimanoglou A, Falip M, Striano P, Cross JH. Refining management strategies for Lennox-Gastaut syndrome: Updated algorithms and practical approaches. Epilepsia Open. 2025;10(1):85-106. doi:10.1002/epi4.13075

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