Can lissencephaly present with seizures in children?

Lissencephaly and Seizures in Children

Yes, lissencephaly characteristically presents with seizures in children, with nearly all patients developing drug-resistant epilepsy, typically beginning within the first 6 months of life. 1, 2

Clinical Presentation

Seizures are a hallmark feature of lissencephaly, occurring in virtually all affected children:

• All but two patients in a cohort of 47 genetically confirmed lissencephaly cases developed epilepsy 2
• Median age at seizure onset is 6 months (range: 2.1-42.0 months) 2
• 82% of patients with LIS1-associated lissencephaly experience seizure onset within the first 6 months of life 1

Seizure Types and Evolution

The epileptogenic phenotype in lissencephaly follows a characteristic pattern:

Early Presentation

• Infantile spasms (epileptic spasms) are the initial seizure type in 70% of patients 2
• These typically begin in the first year of life and represent the most common presenting seizure type 1, 3

Later Evolution

• The seizure phenotype becomes more variable later in infancy and childhood 1
• Generalized tonic-clonic seizures emerge as the predominant seizure type as children age 1
• Focal seizures of various forms also occur 1

Associated Clinical Features

Children with lissencephaly present with a constellation of findings beyond seizures:

• Severe psychomotor retardation and developmental delay 1, 2, 3
• Feeding and swallowing difficulties 3
• Muscle tone abnormalities: early hypotonia progressing to limb hypertonia 3
• Microcephaly 4

Neuroimaging Correlation

MRI is the diagnostic modality of choice for identifying lissencephaly and associated malformations of cortical development 5:

• Lissencephaly is characterized by absent gyri (agyria) or broad gyri (pachygyria) with abnormally thick cortex 5
• The cortex appears thickened with four disorganized layers rather than six normal layers 3
• Associated findings may include corpus callosum dysgenesis and cerebellar/brainstem hypoplasia 4

Prognostic Implications

The presence of epileptic spasms carries significant prognostic weight:

• Patients presenting without epileptic spasms are significantly more likely to reach developmental milestones compared to those with spasms 2
• This underscores the importance of early recognition and aggressive treatment of infantile spasms in lissencephaly 2

Treatment Considerations

Epilepsy in lissencephaly is characteristically drug-resistant 1, 2:

For Infantile Spasms

• Standard hormonal therapy (ACTH or corticosteroids) and/or vigabatrin achieve seizure control in 47% of patients 2

For Later Seizures

• Valproic acid and lamotrigine are most effective, achieving seizure freedom in 20% of patients 2
• Lamotrigine and valproate show good or partial response rates in 88-100% of patients 1
• Vigabatrin and phenobarbital are also effective second-line options 1, 2

Clinical Pitfall

Do not delay neuroimaging in children presenting with early-onset seizures, developmental delay, and feeding difficulties, as this constellation strongly suggests a malformation of cortical development requiring MRI for diagnosis 5, 2. The earlier the diagnosis, the more rapidly appropriate antiseizure management can be initiated, which may improve developmental outcomes 2.