Lennox-Gastaut Syndrome

Lennox-Gastaut syndrome is a severe developmental and epileptic encephalopathy of childhood defined by multiple seizure types (tonic, atonic and atypical absence), a slow spike-and-wave EEG pattern at under 2.5 Hz with paroxysmal fast activity in sleep, and intellectual disability.

It accounts for about 1 to 4% of childhood epilepsies. Onset is typically between 1 and 8 years, with a peak at 3 to 5 years.

Causes. About 70% have a structural, genetic, infectious or metabolic cause (hypoxic injury, malformations of cortical development, tuberous sclerosis, prior infantile spasms, encephalitis, genetic variants); about 25 to 30% are cryptogenic.

Course. Seizures are usually drug resistant, and cognitive and behavioural impairment is common. Mortality is raised from falls, status epilepticus and aspiration.

Pathophysiology.

Diffuse cortical and subcortical network dysfunction produces generalised slow spike wave activity and tonic seizures with sleep related fast rhythms.

The epileptic activity itself contributes to cognitive regression and behavioural disturbance.

• Tonic seizures, mainly in sleep, with axial stiffening.
• Atonic or drop attacks, with injury risk, and atypical absences with slow onset and offset.
• Frequent episodes of non-convulsive status, myoclonic and generalised tonic clonic seizures.
• Developmental delay or regression, behaviour problems and sleep disturbance.

Red flags.

• Non-convulsive status with drowsiness and fluctuating awareness.
• Worsening seizures after an intravenous benzodiazepine (tonic status).
• Head injury from drop attacks.

• EEG: slow (under 2.5 Hz) generalised spike-and-wave in wakefulness and paroxysmal fast activity (10 Hz) in sleep, with a slow background.
• MRI for aetiology; genetic panel or microarray, metabolic tests and sometimes cerebrospinal fluid tests.
• Developmental and neuropsychological assessment, sleep studies and swallow assessment.

Differential diagnosis. Epilepsy with myoclonic atonic seizures, Dravet syndrome, atypical benign partial epilepsy, continuous spike wave in sleep, progressive myoclonic epilepsies and non-epileptic events.

• Treatment is combination therapy, with few seizure free outcomes; the aim is fewer seizures, fewer injuries and better quality of life.
• Sodium valproate first line: initial 10 to 15 mg/kg orally daily in 2 divided doses, increased by 5 to 10 mg/kg weekly to a usual 20 to 30 mg/kg daily. Maximum 60 mg/kg daily. Monitor liver function, full blood count, platelets, ammonia (if drowsy) and weight. Avoid in liver disease, mitochondrial disease (including POLG variants), urea cycle disorders and porphyria. Contraindicated in girls and women of childbearing potential unless no alternative works and a pregnancy prevention programme is in place.
• Lamotrigine add on: with valproate, 0.15 mg/kg orally once daily for 2 weeks, then 0.3 mg/kg daily for 2 weeks, then increases of 0.3 mg/kg every 1 to 2 weeks to a usual 1 to 5 mg/kg daily; without valproate, 0.3 mg/kg daily for 2 weeks, then 0.6 mg/kg daily for 2 weeks, then increases of 0.6 mg/kg every 1 to 2 weeks to a usual 5 to 15 mg/kg daily. Maximum 400 mg daily. Monitor rash and Stevens-Johnson syndrome. Reduce dose in hepatic impairment.
• Clobazam add on: body weight 30 kg or under, 5 mg orally daily, increased to 10 mg daily at day 7 and 20 mg daily at day 14; over 30 kg, 10 mg daily, increased to 20 mg daily at day 7 and 40 mg daily at day 14 (given in 1 or 2 doses). Maximum 20 mg daily (30 kg or under) and 40 mg daily (over 30 kg). Monitor sedation, drooling, behaviour, respiration, tolerance and dependence. Start low in hepatic impairment and in poor CYP2C19 metabolisers (start 5 mg daily and titrate slowly); avoid abrupt withdrawal; caution with opioids.
• Rufinamide add on for age 4 years and over: 10 mg/kg orally daily in 2 divided doses with food, increased by about 10 mg/kg every 2 days to a target of 45 mg/kg daily (maximum 3200 mg daily). Monitor QT interval (contraindicated in familial short QT), rash and hypersensitivity. Avoid in severe hepatic impairment; no renal adjustment; reduce dose with valproate (start 10 mg/kg or lower); reduces hormonal contraceptive efficacy.
• Cannabidiol add on for age 2 years and over: 2.5 mg/kg orally twice daily for 1 week, then 5 mg/kg twice daily, increased weekly in steps of 2.5 mg/kg twice daily to a maximum of 10 mg/kg twice daily. Monitor ALT, AST and bilirubin before treatment and at 1, 3 and 6 months, and mood, sleep and sedation. Reduce the dose in moderate hepatic impairment and avoid in severe impairment; reduce doses of clobazam if sedation occurs.
• Avoid carbamazepine, oxcarbazepine and vigabatrin, and use intravenous benzodiazepines with caution because they can precipitate tonic status.
• Non-drug therapy: ketogenic diet, vagus nerve stimulation and corpus callosotomy for drop attacks.
• Rescue medication plan for prolonged seizures, with a written emergency plan.

Monitoring. Review every 3 months; EEG as needed; monitor cognition, behaviour and bone health.

Referral and escalation. Paediatric epilepsy centre for all children; early referral for surgical or diet therapy.

Special groups. Adolescents and adults: transition to adult epilepsy and learning disability services. Girls: avoid valproate where possible.