What are the typical presentation and treatment options for Lennox-Gastaut syndrome (Epileptic Encephalopathy)?

Lennox-Gastaut Syndrome: Clinical Presentation and Treatment

Clinical Presentation

Lennox-Gastaut syndrome is a profoundly impairing developmental and epileptic encephalopathy characterized by a triad of multiple drug-resistant seizure types (which must include tonic seizures), specific EEG abnormalities, and intellectual disability, with typical onset before age 8 years. 1, 2, 3

Core Diagnostic Features

Seizure Types:

• Tonic seizures are mandatory for diagnosis, though they may not be present at initial onset 3, 4
• Drop attacks (atonic or tonic seizures causing sudden falls) are characteristic and among the most injurious seizure types 5, 6
• Atypical absence seizures with altered awareness 6, 4
• Myoclonic seizures with brief muscle jerks 6
• Focal seizures may also occur 6
• Generalized tonic-clonic seizures are common 6, 7

EEG Characteristics:

• Slow spike-wave complexes (classically <2.5 Hz) during wakefulness 1, 2, 3
• Generalized paroxysmal fast activity (10-20 Hz) during sleep 1, 6
• Background slowing indicating diffuse cerebral dysfunction 6
• Focal or multifocal epileptiform discharges may be present 6
• Note that EEG features can evolve over time, particularly in adult patients, and are not pathognomonic 6, 3

Cognitive and Behavioral Impairment:

• Intellectual disability is a defining feature, though severity varies 1, 2, 3
• Progressive cognitive decline may occur 2
• Behavioral disturbances and psychiatric comorbidities are common 2, 4

Etiology

• Identifiable causes (genetic, structural, metabolic) account for 65-75% of cases 2
• Unknown/cryptogenic causes in 25-35% 2, 3
• May evolve from other epilepsy syndromes, particularly infantile spasms (West syndrome) 4

Diagnostic Considerations

For equivocal cases:

• Extended EEG monitoring during sleep is essential to capture paroxysmal fast activity 6
• Video-EEG monitoring helps characterize seizure semiology 6
• [18F]FDG PET may show variable tracer uptake patterns and can assist in surgical planning when unilateral focal hypometabolism is present 1

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Treatment Approach

The primary treatment goal is reduction in frequency of the most incapacitating seizures—particularly drop attacks and tonic-clonic seizures—as complete seizure control is rarely achievable. 2, 3

First-Line Pharmacotherapy

For newly diagnosed LGS, valproate is the recommended first-line treatment. 4

If valproate monotherapy is ineffective:

1. Add lamotrigine as first adjunctive therapy 4
2. If inadequate response, add rufinamide as second adjunctive therapy 4

Second-Line Pharmacotherapy

If seizure control remains suboptimal after valproate, lamotrigine, and rufinamide, consider the following adjunctive options (listed alphabetically, as evidence is more limited): 4

• Cannabidiol (highly purified) - newer agent with novel mechanism 4
• Clobazam - effective across multiple seizure types 6, 4
• Felbamate - particularly effective for GTCS 7
• Fenfluramine - newer agent with novel mechanism, effective for GTCS 4, 7
• Topiramate - FDA-approved for LGS, effective across seizure types 5, 2, 6, 7

Additional options with varying evidence:

• Levetiracetam 2
• Zonisamide 2, 7
• Lacosamide (particularly for GTCS) 7
• Perampanel (for GTCS and myoclonic seizures) 7
• Brivaracetam (for myoclonic seizures, but may worsen atypical absence) 7

Critical prescribing principle: Use no more than two ASMs together whenever possible to minimize polypharmacy complications. 4

Seizure-Type-Specific Treatment Considerations

For atonic seizures (drop attacks):

• Corpus callosotomy shows superior efficacy 7
• Vagus nerve stimulation is highly effective 7

For generalized tonic-clonic seizures:

• Felbamate, lamotrigine, topiramate, fenfluramine, lacosamide, and perampanel show favorable responses 7

For myoclonic seizures:

• Clonazepam, topiramate, zonisamide, brivaracetam, and perampanel are preferred 7
• Neuromodulation and corpus callosotomy show limited effectiveness 7

For atypical absence seizures:

• Valproate, topiramate, and rufinamide may be effective 7
• Avoid brivaracetam and perampanel as they show poor responses 7

Nonpharmacological Interventions

These should be used in conjunction with ASM therapy, not as alternatives: 4

Ketogenic Diet:

• Effective and well-tolerated treatment option 2
• Shows broad efficacy across seizure types 7

Vagus Nerve Stimulation (VNS):

• Offers reasonable seizure improvement 2
• Most effective for atonic and tonic seizures 7
• Less consistent for GTCS and focal seizures 7

Corpus Callosotomy:

• Palliative surgical procedure targeting the most injurious seizures 2
• Superior efficacy for atonic seizures (drop attacks) 7
• Also effective for tonic seizures 7
• Should be considered for patients with drug-resistant drop attacks 2

Emerging Neuromodulation:

• Deep brain stimulation (DBS) and responsive neurostimulation (RNS) show promise, particularly for tonic and GTCS 7
• Further investigation needed 7

Resective Epilepsy Surgery:

• Consider when focal hypometabolism on PET correlates with ictal EEG findings 1
• Demonstrates broad efficacy across seizure types when appropriate candidate identified 7

Management of Established LGS in Adults

For patients with LGS that evolved from another epilepsy syndrome:

• Transition to valproate if not already prescribed 4
• Then follow the same treatment algorithm as newly diagnosed LGS 4

For older patients with established LGS:

• Review at least annually by an experienced neurologist 4
• Reassess seizure types, as these may evolve over time 6
• Consider EEG changes that occur with aging 6

Common Pitfalls

• Missing the diagnosis in adults due to evolution of EEG patterns and seizure semiology over time 6
• Excessive polypharmacy without clear benefit—limit to two ASMs when possible 4
• Delaying nonpharmacological interventions such as ketogenic diet or VNS when medications fail 2, 4
• Not recognizing that tonic seizures may not be present at onset, leading to delayed diagnosis 3
• Assuming EEG features are pathognomonic—they are supportive but not definitive 3

Prognosis

The long-term outcome for LGS is generally poor, with persistent adverse effects on intellectual development, social functioning, and independent living 2. Drug resistance occurs in the majority of patients 1, 2, and complete seizure freedom with resolution of cognitive dysfunction is rarely achievable 2, 3.