Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy.

OBJECTIVE: Somatic variants are a recognized cause of epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants may underlie a wider range of focal epilepsy, including nonlesional focal epilepsy (NLFE). Through genetic analysis of brain tissue, we evaluated the role of somatic variation in focal epilepsy with and without MCD. METHODS: We identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequencing of DNA from epilepsy surgery specimens and leukocytes from 18 individuals with NLFE and 38 with focal MCD. RESULTS: We observed somatic variants in 5 cases in SLC35A2, a gene associated with glycosylation defects and rare X-linked epileptic encephalopathies. Nonsynonymous variants in SLC35A2 were detected in resected brain, and absent from leukocytes, in 3 of 18 individuals (17%) with NLFE, 1 female and 2 males, with variant allele frequencies (VAFs) in brain-derived DNA of 2 to 14%. Pathologic evaluation revealed focal cortical dysplasia type Ia (FCD1a) in 2 of the 3 NLFE cases. In the MCD cohort, nonsynonymous variants in SCL35A2 were detected in the brains of 2 males with intractable epilepsy, developmental delay, and magnetic resonance imaging suggesting FCD, with VAFs of 19 to 53%; Evidence for FCD was not observed in either brain tissue specimen. INTERPRETATION: We report somatic variants in SLC35A2 as an explanation for a substantial fraction of NLFE, a largely unexplained condition, as well as focal MCD, previously shown to result from somatic mutation but until now only in PI3K-AKT-mTOR pathway genes. Collectively, our findings suggest a larger role than previously recognized for glycosylation defects in the intractable epilepsies. Ann Neurol 2018.

Oxcarbazepine in children with nocturnal frontal-lobe epilepsy.

Nocturnal frontal-lobe epilepsy is characterized by paroxysmal arousals, motor seizures with dystonic or hyperkinetic features, and episodic nocturnal wanderings. Carbamazepine is effective for seizure control in some of these patients, but seizures may be refractory to multiple antiepileptic drugs. We report on eight children between ages 4-16 years with nocturnal frontal-lobe epilepsy who had a dramatic response to oxcarbazepine at standard recommended doses, some of whom were refractory to previous antiepileptic medications. Brain magnetic resonance imaging, routine electroencephalogram, and prolonged, continuous video-electroencephalogram telemetry were performed in all children. Nocturnal frontal-lobe epilepsy was diagnosed by demonstrating ictal electroencephalogram changes originating from the frontal lobes. The children were followed for response of seizures to oxcarbazepine, side effects, and routine blood tests, including serum 10-monohydroxide derivative levels. The mean oxcarbazepine dose was 30.4 mg/kg/day +/- 11.7 (mean +/- SD); the mean 10-monohydroxide level was 23.1 microg/mL +/- 8.6 (mean +/- SD). Seizures improved within 4 days of oxcarbazepine initiation in six children, whereas two children required higher doses. Their follow-up has ranged from 12 to 24 months, without seizure recurrence or serious side effects. Our patients demonstrate the efficacy of oxcarbazepine for nocturnal hyperkinetic seizures in children with nocturnal frontal-lobe epilepsy.

Electrode localization for planning surgical resection of the epileptogenic zone in pediatric epilepsy.

PURPOSE: In planning for a potentially curative resection of the epileptogenic zone in patients with pediatric epilepsy, invasive monitoring with intracranial EEG is often used to localize the seizure onset zone and eloquent cortex. A precise understanding of the location of subdural strip and grid electrodes on the brain surface, and of depth electrodes in the brain in relationship to eloquent areas is expected to facilitate pre-surgical planning. METHODS: We developed a novel algorithm for the alignment of intracranial electrodes, extracted from post-operative CT, with pre-operative MRI. Our goal was to develop a method of achieving highly accurate localization of subdural and depth electrodes, in order to facilitate surgical planning. Specifically, we created a patient-specific 3D geometric model of the cortical surface from automatic segmentation of a pre-operative MRI, automatically segmented electrodes from post-operative CT, and projected each set of electrodes onto the brain surface after alignment of the CT to the MRI. Also, we produced critical visualization of anatomical landmarks, e.g., vasculature, gyri, sulci, lesions, or eloquent cortical areas, which enables the epilepsy surgery team to accurately estimate the distance between the electrodes and the anatomical landmarks, which might help for better assessment of risks and benefits of surgical resection. RESULTS: Electrode localization accuracy was measured using knowledge of the position of placement from 2D intra-operative photographs in ten consecutive subjects who underwent intracranial EEG for pediatric epilepsy. Average spatial accuracy of localization was 1.31 ± 0.69 mm for all 385 visible electrodes in the photos. CONCLUSIONS: In comparison with previously reported approaches, our algorithm is able to achieve more accurate alignment of strip and grid electrodes with minimal user input. Unlike manual alignment procedures, our algorithm achieves excellent alignment without time-consuming and difficult judgements from an operator.