Colleen D'Arcy | Search PubMed

PubMed2026

Deep tissue sequencing improves genetic diagnostic yield in focal cortical dysplasia.

Focal cortical dysplasias (FCDs) are malformations of cortical development associated with drug-resistant focal epilepsy. We analyzed surgical tissue from 25 consecutive cases recruited from adult and pediatric epilepsy surgery programs. We performed high-depth sequencing of lesional tissue, validated somatic variants using droplet digital PCR or amplicon sequencing, and investigated genotype-phenotype correlations. A pathogenic or likely pathogenic variant was detected in 64% (n = 16/25) of cases. Of these, five cases with FCDIIa or FCDIIb had germline variants in NPRL3 (n = 3) or DEPDC5 (n = 2). Somatic variants were identified in 44% (n = 11/25) of cases. The genetic yield for FCDIIb was 77% of cases having a pathogenic mTOR pathway variant detected (n = 10/13), and for FCDIIa 66% (n = 6/9). High depth sequencing approaches allowed detection of somatic variants with very low (down to 0.4%) variant allele fractions (VAFs). No pathogenic variants were detected in 3 cases with FCDI. 62% (n = 15/24) of the cases with ≥12 months follow up experienced a favourable seizure outcome (Engel 1-2) following surgery. Of note, n = 9 patients required repeat surgery to resect residual dysplasia. Determining a genetic diagnosis reveals aetiology and paves the way to precision therapies that may benefit those with FCD who do not respond to current treatments.

Humans↗

PubMed2026

Late-onset epileptic spasms: presentation, aetiology and outcome.

Late-onset epileptic spasms (LOES) are epileptic spasms (ES) commencing after age 12 months, often misdiagnosed and having uncertain relationship to infantile spasms. Previous studies of mostly small LOES cohorts frequently reported 'cryptogenic' aetiologies. We studied the presentations, aetiologies, treatment responses and outcomes in a large LOES cohort, evaluated with modern neuroimaging and genomic testing. In this retrospective cohort study, 62 children with video-confirmed epileptic spasms, diagnosed between 2011 and 2021, were included. All had epileptiform activity on EEG, but none had hypsarrhythmia. Median age at epileptic spasms onset was 23 months (range 1-15 years) and median delay to diagnosis was 8 months (interquartile range: 3-15). Only 24% children were correctly diagnosed at presentation, common misdiagnoses being myoclonic epilepsies and non-epileptic phenomenon. Aetiology was identified in 95%. Structural-malformative aetiologies were present in 63% (most commonly focal cortical dysplasia and mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy). Other aetiologies were structural-acquired in 13% (mostly postnatal stroke and CNS infections), genetic in 13% (mostly intragenic variants and chromosomopathies) and oncological in 6% (history of leukaemia, two with CNS involvement). Children with structural aetiologies often had normal development prior to onset of epileptic spasms, a later median age of epileptic spasms onset and were more likely to have asymmetric or subtle epileptic spasms and additional seizures prior to epileptic spasms. Epileptic spasms ceased in 29% children treated with prednisolone, most having genetic aetiologies and in 35% treated with vigabatrin, all having structural-malformative aetiologies. Apart from clobazam, which was effective in 17% of children, all other antiseizure medications, vagus nerve stimulation and ketogenic diet therapy were ineffective. Epileptic spasms ceased in 86% (18/21) of children who underwent epilepsy surgery. At median follow-up of 10.3 years, 53% children were free of all seizures and 76% were free of epileptic spasms. More children with unilateral structural-malformative aetiologies achieved seizure freedom than other aetiologies, most commonly following surgery but occasionally following treatment with vigabatrin or clobazam. Impairment of cognitive function or adaptive behaviour (formally assessed in 90%) was significantly more common in children with genetic than structural aetiologies, and in children with ongoing seizures than seizure freedom. Among children who underwent epilepsy surgery, 62% achieved average or low-average adaptive functioning or normal intellectual capacity. This study highlights the importance of prompt recognition of epileptic spasms in older children for improved seizure and developmental outcomes. Brain malformations and insults are the predominant causes of LOES, and when unilateral, respond best to epilepsy surgery.

cognitive outcome↗