Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations ...of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT-mTOR-signalling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly or focal cortical dysplasia. We evaluated samples from 123 children with hemimegalencephaly (n = 16), focal cortical dysplasia type I and related phenotypes (n = 48), focal cortical dysplasia type II (n = 44), or focal cortical dysplasia type III (n = 15). We performed high-depth exome sequencing in brain tissue-derived DNA from each case and identified somatic single nucleotide, indel and large copy number variants. In 75% of individuals with hemimegalencephaly and 29% with focal cortical dysplasia type II, we identified pathogenic variants in PI3K-AKT-mTOR pathway genes. Four of 48 cases with focal cortical dysplasia type I (8%) had a likely pathogenic variant in SLC35A2. While no other gene had multiple disease-causing somatic variants across the focal cortical dysplasia type I cohort, four individuals in this group had a single pathogenic or likely pathogenic somatic variant in CASK, KRAS, NF1 and NIPBL, genes previously associated with neurodevelopmental disorders. No rare pathogenic or likely pathogenic somatic variants in any neurological disease genes like those identified in the focal cortical dysplasia type I cohort were found in 63 neurologically normal controls (P = 0.017), suggesting a role for these novel variants. We also identified a somatic loss-of-function variant in the known epilepsy gene, PCDH19, present in a small number of alleles in the dysplastic tissue from a female patient with focal cortical dysplasia IIIa with hippocampal sclerosis. In contrast to focal cortical dysplasia type II, neither focal cortical dysplasia type I nor III had somatic variants in genes that converge on a unifying biological pathway, suggesting greater genetic heterogeneity compared to type II. Importantly, we demonstrate that focal cortical dysplasia types I, II and III are associated with somatic gene variants across a broad range of genes, many associated with epilepsy in clinical syndromes caused by germline variants, as well as including some not previously associated with radiographically evident cortical brain malformations.
Our objective is to characterize the long-term course of Glut1 deficiency syndrome. Longitudinal outcome measures, including Columbia Neurological Scores, neuropsychological tests, and adaptive ...behavior reports, were collected for 13 participants with Glut1 deficiency syndrome who had been followed for an average of 14.2 (range = 8.9-23.6) years. A parent questionnaire assessed manifestations throughout development. The 6-Minute Walk Test captured gait disturbances and triggered paroxysmal exertional dyskinesia. All longitudinal outcomes remained stable over time. Epilepsy dominated infancy and improved during childhood. Dystonia emerged during childhood or adolescence. Earlier introduction of the ketogenic diet correlated with better long-term outcomes on some measures. Percent-predicted 6-Minute Walk Test distance correlated significantly with Columbia Neurological Scores. We conclude that Glut1 deficiency syndrome is a chronic condition, dominated by epilepsy in infancy and by movement disorders thereafter. Dietary treatment in the first postnatal months may effect improved outcomes, emphasizing the importance of early diagnosis and treatment.
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
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•LVFA at ictal onset is associated with good surgical outcomes in children.•Consistent IOP morphology is associated with good surgical outcomes in children.•LVFA at ictal onset is ...less common in younger children during IEEG recording.
We aimed to classify ictal onset patterns (IOPs) in pediatric patients undergoing intracranial electroencephalography (IEEG) to guide surgery for refractory epilepsy. We aimed to determine if morphology of IOPs can predict surgical outcome.
We performed a retrospective review of pediatric patients who underwent epilepsy surgery guided by subdural IEEG from 2007 to 2016. IEEG seizures were reviewed by a blinded epileptologist. Data was collected on outcomes.
Twenty-three patients with 784 seizures were included. Age at seizure onset was 0.2–11 (mean 4.3, standard deviation 3.2) years. Age at time of IEEG was 4–20 (mean 13.5, standard deviation 4.4) years. Five distinct IOPs were seen at seizure onset: A) Low voltage fast activity (LVFA) with spread to adjacent electrodes (n = 7 patients, 30%), B) Burst of LVFA followed by electrodecrement (n = 12 patients, 52%), C) Burst of rhythmic spike waves (RSW) followed by electrodecrement (n = 9 patients, 39%), D) RSW followed by LVFA (n = 7 patients, 30%), E) Rhythmic spikes alone (n = 10 patients, 43%). Twelve patients (52%) had the same IOP type with all seizures. When the area of the IOP was resected, 14 patients (61%) had Engel I outcomes. Patients who had LVFA seen within their predominant IOP type were more likely to have good surgical outcomes (odds ratio 7.50, 95% confidence interval 1.02–55.0, p = 0.05). Patients who had only one IOP type were more likely to have good outcomes than patients who had multiple IOP types (odds ratio 12.6, 95% confidence interval 1.19–134, p = 0.04). Patients who had LVFA in their predominant IOP type were older than patients who did not have LVFA (mean age 15.0 vs. 9.9 years, p = 0.02).
LVFA at ictal onset and all seizures having the same IOP morphology are associated with increased likelihood of surgical success in children, but LVFA is less common in children who are younger at the time of IEEG.
Background: Nonconvulsive status epilepticus (NCSE) is a highly heterogeneous clinical condition that is understudied in the pediatric population.
Objective: To analyze the epidemiological, clinical, ...and electroencephalograpic features in pediatric patients with NCSE.
Methods: We identified 19 pediatric patients with NCSE from the epilepsy database of the Comprehensive Epilepsy Center at, Columbia University between June 2000 and December 2003. Continuous electroencephalographic (EEG) monitoring was analyzed and chart review was performed.
Results: The patients ranged from 1 month old to 17 years of age. Five patients developed NCSE following convulsive status epilepticus (CSE), and a further 12 patients developed NCSE after brief convulsions. Two developed NCSE as the first manifestation during a comatose state following hypoxic events. Acute hypoxic‐ischemic injury was the most frequent etiology of NCSE in our population (5 of 19; 26%), followed by exacerbation of underlying neurometabolic disease (4 of 19; 21%), acute infection (3 of 19; 16%), change in antiepileptic drug regimen (3 of 19;16%), refractory epilepsy (2 of 19; 11%) and intracranial hemorrhage (2 of 19; 11%). Six patients had associated periodic lateralized epileptiform discharges (PLEDs), one had generalized periodic epileptiform discharges (GPEDs). Five (5 of 19; 26%) patients died of the underlying acute medical illness. Periodic discharges were associated with worse outcome.
Conclusion: The majority of our patients with NCSE had preceding seizures in the acute setting prior to the diagnosis of NCSE, though most of these seizures were brief, isolated convulsions (12 patients) rather than CSE (five patients). Prolonged EEG monitoring to exclude NCSE may be warranted in pediatric patients even after brief convulsive seizures. Prompt recognition and treatment may be necessary to improve neurological outcome.
This study aimed to assess the clinical outcome and outcome predictive factors in pediatric epilepsy patients evaluated with stereo-electroencephalography (SEEG).
Thirty-eight patients who underwent ...SEEG implantation at the Pediatric Epilepsy Center in New York Presbyterian Hospital between June 2014 and December 2019 were enrolled for retrospective chart review. Postoperative seizure outcomes were evaluated in patients with at least 12-months follow up. Meta-analysis was conducted via electronic literature search of data reported from 2000 to 2020 to evaluate significant surgical outcome predictors for SEEG evaluation in the pediatric population.
In the current case series of 25 postsurgical patients with long-term follow up, 16 patients (64.0%) were seizure free. An additional 7 patients (28.0%) showed significant seizure improvement and 2 patients (8.0%) showed no change in seizure activity. Patients with nonlesional magnetic resonance imaging (MRI) achieved seizure freedom in 50% (5/10) of cases. By comparison, 73% (11/15) of patients with lesional MRI achieved seizure freedom.
Out of 12 studies, 158 pediatric patients were identified for inclusion in a meta-analysis of the effectiveness of SEEG. Seizure freedom was reported 54.4% (n = 86/158) of patients at last follow up. Among patients with nonlesional MRI, 45% (n = 24) achieved seizure freedom compared with patients with lesional MRI findings (61.2%, n:= 60) (p = 0.02). The risk for seizure recurrence was 2.15 times higher 95% confidence interval CI 1.06–4.37, p = 0.033 in patients diagnosed with nonlesional focal epilepsy compared to those with lesional epilepsy 1.49 (95% CI 1.06–2.114, p = 0.021.
Evaluation by SEEG implantation in pediatric epilepsy is effective in localizing the epileptogenic zone with favorable outcome. Presence of a non-lesional brain MRI was associated with lower chances of seizure freedom. Further research is warranted to improve the efficacy of SEEG in localizing the epileptogenic zone in pediatric patients with non-lesional brain MRI.
•Stereo-electroencephalography (SEEG) is increasingly being used in the pediatric epilepsy patients.•Localization of the epileptogenic zone was achieved using SEEG in patients who failed previous epilepsy surgery.•Nonlesional brain MRI in preoperative evaluation was shown to be a negative prognostic factor.•Better approaches to nonlesional brain MRI are needed when using SEEG for preoperative evaluation.
A variety of autoantibodies have been identified with complex neurological disorders including limbic encephalitis. The underlying trigger for the immune‐mediated process and the role of ...autoantibodies in the pathogenesis of limbic encephalitis remain to be clarified. Here, we report a 16‐year‐old female who was diagnosed with acute‐onset non‐neoplastic limbic encephalitis. The initial treatment with pulse doses of i.v. methylprednisolone improved the neurological symptoms. During the next 12 months, progressive decline was reported in her academic functioning and seizure control. Additional diagnostic evaluation revealed no evidence of malignancy or central nervous system infection but circulating anti‐GAD antibodies were present in the serum and cerebrospinal fluid. Intravenous gammaglobulin infusion was initiated and continued monthly. Intravenous and oral steroids were added to the intravenous immunoglobulin treatment because of the worsening course and seizures, despite treatment with antiepileptic medications. Screening for quantitative immunoglobulins demonstrated hypogammaglobulinaemia with low immunoglobulin M and G in addition to low immunoglobulin A levels. There was a lack of protective pneumococcal antibody titers before and after immunization. Therefore, common variable immunodeficiency was suspected despite there being no history of recurrent infections. To our knowledge, this is the first report describing a possible link between immune‐mediated limbic encephalitis and immune deficiency.
Patients with medically refractory localization-related epilepsy (LRE) may be candidates for surgical intervention if the seizure onset zone (SOZ) can be well localized. Stereoelectroencephalography ...(SEEG) offers an attractive alternative to subdural grid and strip electrode implantation for seizure lateralization and localization; yet there are few series reporting the safety and efficacy of SEEG in pediatric patients.
The authors review their initial 3-year consecutive experience with SEEG in pediatric patients with LRE. SEEG coverage, SOZ localization, complications, and preliminary seizure outcomes following subsequent surgical treatments are assessed.
Twenty-five pediatric patients underwent 30 SEEG implantations, with a total of 342 electrodes placed. Ten had prior resections or ablations. Seven had no MRI abnormalities, and 8 had multiple lesions on MRI. Based on preimplantation hypotheses, 7 investigations were extratemporal (ET), 1 was only temporal-limbic (TL), and 22 were combined ET/TL investigations. Fourteen patients underwent bilateral investigations. On average, patients were monitored for 8 days postimplant (range 3-19 days). Nearly all patients were discharged home on the day following electrode explantation. There were no major complications. Minor complications included 1 electrode deflection into the subdural space, resulting in a minor asymptomatic extraaxial hemorrhage; and 1 in-house and 1 delayed electrode superficial scalp infection, both treated with local wound care and oral antibiotics. SEEG localized the hypothetical SOZ in 23 of 25 patients (92%). To date, 18 patients have undergone definitive surgical intervention. In 2 patients, SEEG localized the SOZ near eloquent cortex and subdural grids were used to further delineate the seizure focus relative to mapped motor function just prior to resection. At last follow-up (average 21 months), 8 of 15 patients with at least 6 months of follow-up (53%) were Engel class I, and an additional 6 patients (40%) were Engel class II or III. Only 1 patient was Engel class IV.
SEEG is a safe and effective technique for invasive SOZ localization in medically refractory LRE in the pediatric population. SEEG permits bilateral and multilobar investigations while avoiding large craniotomies. It is conducive to deep, 3D, and perilesional investigations, particularly in cases of prior resections. Patients who are not found to have focally localizable seizures are spared craniotomies.
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