Lennox-Gastaut Syndrome (LGS) — Treatment

Overview

1. Multiple seizure types — generalized tonic, atonic (drop attacks), and atypical absence seizures
2. EEG abnormalities — slow (<2.5 Hz) spike-and-wave discharges in waking; paroxysmal fast activity (~10 Hz) in sleep
3. Cognitive dysfunction / developmental delay

Pharmacological Treatment

First-Line / Cornerstone Agents

Valproate + lamotrigine + a benzodiazepine is the most widely used combination for atonic seizures in LGS. — Katzung's Basic and Clinical Pharmacology, 16th Ed.

LGS-Specific Approved Adjuncts

Rufinamide

• Triazole derivative; sodium channel blocker
• FDA/EMA approved specifically for LGS
• Effective against all seizure types, especially atonic seizures
• Dosing: Children: start 10 mg/kg/day in 2 divided doses → up to 45 mg/kg/day (max 3200 mg/day); Adults: 400–800 mg/day → max 3200 mg/day; take with food
• Key interaction: valproate reduces rufinamide clearance — may require 50% dose reduction of rufinamide in children
• Common SEs: somnolence, vomiting

Cannabidiol (CBD)

• Non-psychoactive phytocannabinoid; FDA-approved for LGS seizures (also Dravet syndrome, tuberous sclerosis complex)
• Mechanism: Not via CB1/CB2 receptors; mechanism unknown
• Dosing: Titrate to 10 mg/kg/day in 2 divided doses; may increase to 20–25 mg/kg/day; administer with food (especially high-fat meal — 4–5× bioavailability increase)
• Key interaction: cannabidiol inhibits CYP2C19 → 3-fold increase in N-desmethylclobazam levels; reduce clobazam dose to avoid excessive sedation; concurrent valproate increases risk of liver function abnormalities
• Main SEs: somnolence (25%), decreased appetite (19%), diarrhea (19%), fatigue (13%), dose-dependent LFT elevations

Felbamate

• Effective for LGS, but use is severely restricted due to rare but serious risk of aplastic anemia and hepatic failure
• Reserved for refractory patients where benefits outweigh risks

Other Used Agents

• Clonazepam / other benzodiazepines — used as part of combination therapy
• Zonisamide — used as adjunct in some centers
• Perampanel — AMPA-receptor antagonist; has been used adjunctively

Note: Sodium channel blockers (carbamazepine, oxcarbazepine, phenytoin) should generally be avoided in LGS — they can worsen atonic and myoclonic seizures.

Non-Pharmacological Treatment

Ketogenic Diet

• High-fat, low-carbohydrate diet inducing ketosis
• Established as adjunctive therapy in LGS; effective especially in drug-resistant cases
• Listed as a treatment option in The Harriet Lane Handbook (23rd ed.) and Bradley & Daroff's Neurology
• Modified Atkins diet is an alternative variation

Corpus Callosotomy

• Surgical disconnection of the corpus callosum
• Specifically effective for disabling tonic or atonic (drop) seizures in LGS
• Indicated when antiseizure medications have failed and drop attacks are the predominant debilitating seizure type
• Harrison's (2025): "corpus callosotomy has been shown to be effective for disabling tonic or atonic seizures, usually when they are part of a mixed-seizure syndrome (e.g., Lennox-Gastaut syndrome)"

Vagus Nerve Stimulation (VNS)

• Implanted programmable pulse generator with electrode on left vagus nerve
• Used for refractory epilepsy including LGS
• Long-term studies support benefit in LGS (e.g., Kostov et al., 2009 — cited in Bradley & Daroff's)

Other Neurostimulation

• Deep brain stimulation (DBS) and responsive neurostimulation (RNS) are being investigated for generalized epilepsies including LGS — referenced as an area of active investigation in Harrison's (2025)
• A 2026 systematic review and meta-analysis (PMID: 41481212) specifically evaluated invasive neuromodulation in LGS

Summary Table (Harriet Lane, 23rd Ed.)

Prognosis

• Harrison's Principles of Internal Medicine, 22nd Ed. (2025)
• Katzung's Basic & Clinical Pharmacology, 16th Ed.
• Bradley and Daroff's Neurology in Clinical Practice
• Goodman & Gilman's The Pharmacological Basis of Therapeutics
• The Harriet Lane Handbook, 23rd Ed.
• Adams and Victor's Principles of Neurology, 12th Ed.