What is Lennox-Gastaut syndrome in children with a history of developmental delays or other seizure disorders, typically between the ages of 2 and 6 years?

Lennox-Gastaut Syndrome: Comprehensive Overview

Definition and Core Features

Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy characterized by the triad of multiple drug-resistant seizure types (which must include tonic seizures), abnormal EEG with slow spike-and-wave discharges, and cognitive/behavioral impairments, typically with onset between ages 1-8 years. 1, 2

Essential Diagnostic Criteria

• Multiple seizure types with mandatory presence of tonic seizures (though these may not be present at initial onset) 1, 2
• Tonic seizures are the most common pattern, particularly nocturnal tonic seizures, but often develop later in the disease course 3
• Atonic seizures causing dangerous drop attacks with high injury risk 4
• Atypical absence seizures 3
• Myoclonic seizures occur less frequently than the three preceding types 3
• Axial seizures (tonic, atonic) are primary patterns 3

EEG Characteristics

• Interictal pattern: High voltage, bifrontal 1.5-2.5 Hz slow spike-and-wave complexes 3
• Ictal pattern: Attenuation with paroxysmal fast activity (10-13 Hz) during seizures 3
• EEG features are not pathognomonic of the disorder, adding diagnostic complexity 1

Etiology and Pathophysiology

Symptomatic vs. Cryptogenic

• Most cases are symptomatic (secondary to underlying brain disorder) rather than cryptogenic (no known cause) 1, 3
• Perinatal events are the predominant factors in symptomatic cases 5

Common Underlying Causes

• Intrauterine infections 3
• Vascular insults to the brain during prenatal/perinatal periods 3
• Migrational abnormalities of the brain 3
• Late effects of CNS infections 3
• Genetic disorders such as tuberous sclerosis 3
• Inherited metabolic disorders 3

Neuroimaging Findings

• Brain MRI should be obtained to identify structural abnormalities in all suspected cases 5
• Structural lesions may include malformations of cortical development 6

Clinical Presentation and Age of Onset

Typical Onset Pattern

• Classical onset occurs before age 8 years, though some cases with later onset have been described 2
• Syndrome typically begins between ages 1-8 years 3
• Onset specifically between ages 2-6 years is most common in children with developmental delays or other seizure disorders 1
• The syndrome worsens during latency and frequently persists into adulthood 3

Evolution from Other Epilepsies

• LGS may evolve from other types of epilepsy rather than presenting de novo 2
• Early diagnostic challenge includes distinguishing LGS from severe myoclonic epilepsy of infancy (Dravet syndrome) or myoclonic-astatic epilepsy (Doose syndrome), as seizure patterns overlap at onset 3

Cognitive and Behavioral Manifestations

Progressive Cognitive Decline

• Most patients develop moderate intellectual disability within a few years of syndrome onset 3
• Cognitive impairment is a defining feature, though the degree varies 1, 2
• Learning difficulties are universal and most patients require significant support, often in residential care 2

Behavioral Problems

• Many develop behavioral problems including inattention, hyperactivity, and aggression 3
• Behavioral impairments contribute significantly to overall disease burden 2

Treatment Resistance and Prognosis

Seizure Control Challenges

• Seizures are profoundly impairing with poor responsiveness to antiepileptic medications 5
• Seizures are frequently resistant to multiple antiepileptic drugs 4
• Long-term outcome for seizure control is poor for most patients 1, 3
• The prognosis for complete seizure control remains poor despite newer therapies 4

Mortality and Morbidity

• Early identification is critical because the syndrome is profoundly impairing 5
• Atonic seizures result in dangerous drop attacks with risks of serious injury and impairment of quality of life 4
• People with LGS often fall and injure themselves due to seizure-related drops 2

First-Line Pharmacological Management

Initial Treatment Approach

For newly diagnosed LGS, valproate (sodium valproate) is the recommended first-line treatment. 7, 2

• Start valproate as monotherapy initially 2
• If valproate monotherapy is ineffective, add lamotrigine as first adjunctive therapy 2
• If seizures persist, add rufinamide as second adjunctive therapy 2

FDA-Approved Adjunctive Therapies for LGS

Topiramate is FDA-approved for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in adults and pediatric patients ages 2-16 years. 8

Topiramate Dosing for LGS

• Pediatric patients (ages 2-16 years): Recommended total daily dose is approximately 5-9 mg/kg/day in two divided doses 8
• Titration schedule: Begin at 25 mg (or less, based on 1-3 mg/kg/day) nightly for the first week, then increase at 1-2 week intervals by increments of 1-3 mg/kg/day (in two divided doses) 8
• Adults (17 years and over): Recommended dose is 400 mg/day in two divided doses 8
• Adult titration: Initiate at 25-50 mg/day, followed by titration in increments of 25-50 mg/week 8
• Tablets should not be broken due to bitter taste; can be taken without regard to meals 8

Special Populations for Topiramate

• Renal impairment (creatinine clearance <70 mL/min/1.73m²): Use half the usual adult dose; longer time required to reach steady-state 8
• Hemodialysis patients: Supplemental dose may be required as topiramate is cleared 4-6 times faster during dialysis 8
• Hepatic impairment: Plasma concentrations may be increased 8
• Elderly patients: Dosage adjustment necessary if creatinine clearance ≤70 mL/min/1.73m² 8

Additional Evidence-Based Adjunctive Options

If seizure control remains suboptimal after valproate, lamotrigine, and rufinamide, subsequent adjunctive options include (alphabetically): 2

• Cannabidiol (highly purified) - newer agent with novel mechanism 2
• Clobazam 2
• Felbamate 7, 3
• Fenfluramine - newer agent with novel mechanism 2
• Topiramate 7, 3

Polypharmacy Considerations

• Whenever possible, no more than two antisepileptic drugs should be used together 2
• Polytherapy increases risk of medication-related side effects in patients who already have learning disability and developmental delay 9
• Long-term outcome does not appear better with newer antiepileptic drugs compared to earlier drugs or polytherapy 3

Treatment for Evolved LGS

• Patients with LGS that evolved from another epilepsy type who are not already on valproate should be transitioned to valproate, then managed using the same algorithm as newly diagnosed LGS 2

Non-Pharmacological Treatment Options

When to Consider Non-Drug Therapies

When multiple antiepileptic drug trials fail, non-pharmacological treatments should be considered. 4

• Non-pharmacological approaches should be used in conjunction with antisepileptic medication therapy 2

Ketogenic Diet

• Ketogenic diet therapies are an established option for drug-resistant LGS 7, 2, 3, 4
• Should be considered when pharmacological options are exhausted 4

Vagus Nerve Stimulation (VNS)

• VNS is an option for patients with refractory seizures 7, 2, 3, 4
• Can be used in conjunction with antiepileptic medications 2

Surgical Options

• Corpus callosotomy is a surgical option for patients with severe drop attacks and drug-resistant seizures 7, 2, 3, 4
• Epilepsy surgery should be considered when multiple drug trials fail 4

Special Management Considerations

Provoked Seizures and Metabolic Factors

• Acute symptomatic or provoked seizures may be secondary to hypocalcemia, hypomagnesemia, fever, or medications 9
• Hypocalcemia must be ruled out as a precipitating factor, particularly in patients with 22q11.2 deletion syndrome where it can trigger seizures at any age 10
• Correct underlying electrolyte disturbances (hypocalcemia, hypomagnesemia) as primary treatment before or concurrent with antiepileptic therapy 9

Monitoring and Follow-Up

• Older patients with established LGS should be reviewed at least annually by a suitably experienced neurologist 2
• Perform EEG if there is suspicion of seizure activity, with accurate seizure classification using clinical history and EEG to guide medical management 9
• Obtain brain MRI in cases of rapid head growth increase, infantile spasms, changes in neurologic examination, or regression of skills 9

Infantile Spasms Management

• For infantile spasms in LGS patients, consult with a cardiologist before initiating steroid management due to risk of cardiomyopathy 9

Medication Dosing Principles

• Use a "start low, go slow" approach to medication dosing due to lowered seizure threshold and potential for increased medication side effects 9
• Monitor carefully for medication side effects given increased sensitivity in this population 9

Prognostic Factors and Outcomes

Long-Term Cognitive Outcome

• Long-term outcome relative to cognition is poor 3
• Most develop moderate intellectual disability within a few years of onset 3
• Cognitive decline is progressive and inevitable in most cases 1

Quality of Life Impact

• The syndrome results in significant impairment of quality of life 4
• Most patients need substantial support, often requiring residential care 2
• Early intervention may improve mental and behavioral development 5

Seizure Outcome

• Complete seizure freedom is rarely achieved 3, 4
• The addition of newer therapies provides improved hope for some patients and their families, though overall prognosis remains guarded 4

Common Diagnostic Pitfalls

Early Misdiagnosis

• Tonic seizures, thought to be characteristic of LGS, are not present at onset, leading to delayed diagnosis 1
• Seizure patterns overlap with Dravet syndrome and Doose syndrome early in the course 3
• There is debate regarding the precise limits, cause, and diagnosis of the syndrome 1

EEG Interpretation

• EEG features are not pathognomonic of the disorder, requiring clinical correlation 1
• Slow spike-wave complexes must be interpreted in context of clinical seizure patterns 3

Evidence Base Limitations

• Only five double-blind, placebo-controlled clinical trials of antiepileptic drugs have been conducted in LGS 7
• None of these were head-to-head comparison trials 7
• The evidence supporting the use of available treatments is not robust 7
• Many commonly used drugs have little or no supporting evidence from controlled trials 1
• Further long-term randomized controlled trials are required to compare different therapeutic interventions in terms of efficacy and tolerability 4