Lennox-Gastaut syndrome (LGS)

What it is

Lennox-Gastaut syndrome (LGS) is a developmental and epileptic encephalopathy defined by the convergence of three features — multiple seizure types (with tonic seizures essentially mandatory for the diagnosis, plus atonic 'drop' attacks and atypical absences), a characteristic EEG signature (interictal slow spike-and-wave at less than 3 Hz, plus runs of generalised paroxysmal fast activity in non-REM sleep), and intellectual disability that emerges over the course of childhood.

Around a third of children with LGS have a prior history of West syndrome (infantile spasms) that evolved into the LGS pattern, but LGS can also begin de novo in a previously well or developmentally typical child.

Causes

More than half of children with LGS have a structural cause (tuberous sclerosis complex, perinatal hypoxic-ischaemic injury, cortical malformations such as focal cortical dysplasia or polymicrogyria, neurocutaneous syndromes), about 5–10% have a defined metabolic cause, and 20–30% have a genetic cause identifiable on modern panels — most often SCN8A, STXBP1, CHD2, GABRB3, SCN2A, ALG13 or DNM1. A residual minority remain unexplained even after thorough evaluation, though that proportion shrinks every year as genetic testing improves.

How it presents

The seizure picture is the most striking feature:

• Tonic seizures — usually in sleep or just on waking; brief stiffening of the trunk, neck and limbs lasting seconds. Easily missed if subtle; revealed by overnight or daytime nap video-EEG
• Atonic 'drop' seizures — sudden loss of postural tone, the child collapses; head and facial injuries are common and helmets are often worn
• Atypical absences — gradual onset and end, partial loss of awareness, often with subtle myoclonus or automatisms
• Non-convulsive status epilepticus — long episodes of altered awareness with continuous slow spike-and-wave on EEG; occurs in many children at least once and is easy to miss without an EEG
• Generalised tonic-clonic, focal-onset and myoclonic seizures also occur

Diagnosis

The diagnosis combines the clinical seizure picture (especially tonic seizures), the EEG (slow spike-and-wave + GPFA in sleep) and the developmental trajectory. Modern workup includes a high-quality 3-Tesla MRI of the brain, an expanded epilepsy gene panel or trio whole-exome sequencing, and metabolic screening when the picture is atypical.

Current management

There is no curative drug; the goal is to reduce the seizure burden — particularly drop attacks — and to protect cognition and quality of life. Treatment is layered:

• First-line antiseizure medicines: valproate (or sodium valproate), often in combination with lamotrigine or rufinamide. Rufinamide is specifically licensed for drop seizures in LGS.
• Clobazam — long-established add-on, particularly effective for tonic-atonic seizures
• Pharmaceutical-grade cannabidiol (Epidiolex / Epidyolex) — licensed for LGS since 2018 (US) / 2019 (EU). Around 40% of children achieve ≥50% reduction in drop seizures. Used as monotherapy is rare; usually added on
• Fenfluramine (Fintepla) — repurposed serotonergic drug, originally for Dravet, EU/US licensed for LGS in 2022–2023. Drop-seizure reduction of about 25–30% over placebo; risk of pulmonary hypertension and valvular heart disease has not materialised in the modern paediatric dose range, but echocardiography monitoring is required
• Soticlestat (TAK-935) — selective cholesterol-24-hydroxylase inhibitor that lowers brain 24-OH-cholesterol and reduces NMDA receptor over-activation; the SKYWAY (LGS) and SKYLINE (Dravet) Phase 3 trials reported in 2023–2024 with positive but modest results; under regulatory review in late 2025
• Older add-ons: topiramate, zonisamide, perampanel and felbamate (the latter is highly effective but used cautiously because of aplastic anaemia and liver toxicity)
• Sodium-channel blockers (carbamazepine, oxcarbazepine, phenytoin, lamotrigine in some) can worsen tonic and atonic seizures and are often avoided in classic LGS — except for lamotrigine, which is mainstream in LGS
• Ketogenic diet (classical or modified Atkins) — frequently effective in LGS, especially when started early; modified Atkins is more practical for school-age children
• Vagus nerve stimulation (VNS) — 30–50% have meaningful reduction in seizures, with response improving over 12–24 months
• Corpus callosotomy — surgical disconnection of the two hemispheres; the most effective treatment for severe drop attacks when medical therapy fails, with 50–80% reduction in drop seizures in published series
• Targeted surgery for a focal structural cause (e.g. focal cortical dysplasia) can rarely be curative when the imaging-EEG-semiology concordance allows it

Prognosis

LGS is lifelong. Seizures usually persist into adulthood, although the EEG pattern often evolves into multifocal spikes and the tonic seizures become less frequent. Around 5% become seizure-free with medication or after surgery. Cognitive outcome is broadly determined by the underlying cause, the age at which the LGS pattern began, and the seizure burden in the first few years — earlier diagnosis with proactive use of modern treatments may improve cognitive trajectories, though this is still being shown in long-term cohorts.

How an educational review can help

Families managing LGS often juggle four or five medicines, a helmet, a ketogenic diet, frequent EEGs and difficult conversations about quality of life and school placement. An educational review can pull together the most recent evidence — particularly on cannabidiol, fenfluramine, soticlestat and surgery — and help you prepare focused questions for your treating epilepsy team.

It is an educational second opinion — not a diagnosis, treatment or prescription — and it does not replace the care of your child's own clinicians.