Children with seizures and radiological diagnosis of focal cortical dysplasia: can drug-resistant epilepsy be predicted earlier?

Objective: Focal cortical dysplasia (FCD) is a malformation of cortical development and is associated with drug-resistant epilepsy. Standard indication for epilepsy surgery is drug resistance (as defined by the ILAE). Given the high incidence of drug resistance in these children, this delay may not be warranted. The aim of the study was to determine the proportion of patients with a presumed FCD who develop drug resistance, and evaluate post-operative outcomes. Methods: This study incorporated a survey within a regional paediatric epilepsy network and a retrospective database review of a paediatric epilepsy center serving the network to identify children with epilepsy and a presumed FCD on MRI. Results: The survey revealed that 86% of the patients with epilepsy and presumed FCD on MRI within the network were referred to our centre. Of 139 pediatric patients included in the study, 131 (94.2%) had drug-resistant epilepsy. One hundred and ten (83.9%) patients were referred to epilepsy surgery, of whom 97 underwent surgery. Of 92 with one-year postoperative follow-up, 59.8% had an Engel Class 1 (seizure-free) outcome. Concordance of location between MRI and ictal EEG was strongly associated with Engel Class 1 outcome ( p <0.001), as was older age at seizure onset ( p =0.03). Time from diagnosis to surgery, number of medications, type of surgery and histology were not associated with improved outcome. Significance: Our data suggest that most children presenting with seizures and a radiological diagnosis of FCD will develop drug-resistant epilepsy and are candidates for epilepsy surgery. The main outcome predictors are the correlation between MRI and ictal EEG localization and age at onset. This suggests that patients with FCD and epilepsy may be considered for surgery before traditional criteria of drug resistance are met. This change in practice has the potential to improve quality of life and cognitive function, and reduce burden on epilepsy services

Proportion of resected seizure onset zone contacts in pediatric stereo-EEG-guided resective surgery does not correlate with outcome

Objective: We aimed to determine whether the proportion of putative seizure onset zone (SOZ) contacts resected associates with seizure outcome in a cohort of children undergoing stereoelectroencephalography (SEEG)-guided resective epilepsy surgery. / Methods: Patients who underwent SEEG-guided resective surgery over a six-year period were included. The proportion of SOZ contacts resected was determined by co-registration of pre- and post-operative imaging. Outcome was classified as seizure free (SF, Engel class I) or not seizure-free (NSF, Engel class II-IV) at last clinical follow-up. / Results: Twenty-nine patients underwent resection of whom 22 had sufficient imaging data for analysis (median age at surgery of 10 years, range 5–18). Fifteen (68.2%) were SF at median follow-up of 19.5 months (range 12–46). On univariate analysis, histopathology, was the only significant factor associated with SF (p < 0.05). The percentage of defined SOZ contacts resected ranged from 25-100% and was not associated with SF (p = 0.89). In a binary logistic regression model, it was highly likely that histology was the only independent predictor of outcome. / Conclusions: The percentage of SOZ contacts resected was not associated with SF in children undergoing SEEG-guided resective epilepsy surgery. / Significance: Factors such as spatial organisation of the epileptogenic zone, neurophysiological biomarkers and the prospective identification of pathological tissue may therefore play an important role

Epileptogenic Tubers Are Associated with Increased Kurtosis of Susceptibility Values: A Combined Quantitative Susceptibility Mapping and Stereoelectroencephalography Pilot Study

BACKGROUND AND PURPOSE: Prior studies have found an association between calcification and the epileptogenicity of tubers in tuberous sclerosis complex. Quantitative susceptibility mapping is a novel tool sensitive to magnetic susceptibility alterations due to tissue calcification. We assessed the utility of quantitative susceptibility mapping in identifying putative epileptogenic tubers in tuberous sclerosis complex using stereoelectroencephalography data as ground truth. MATERIALS AND METHODS: We studied patients with tuberous sclerosis complex undergoing stereoelectroencephalography at a single center who had multiecho gradient-echo sequences available. Quantitative susceptibility mapping and R2* values were extracted for all tubers on the basis of manually drawn 3D ROIs using T1- and T2-FLAIR sequences. Characteristics of quantitative susceptibility mapping and R2* distributions from implanted tubers were compared using binary logistic generalized estimating equation models designed to identify ictal (involved in seizure onset) and interictal (persistent interictal epileptiform activity) tubers. These models were then applied to the unimplanted tubers to identify potential ictal and interictal tubers that were not sampled by stereoelectroencephalography. RESULTS: A total of 146 tubers were identified in 10 patients, 76 of which were sampled using stereoelectroencephalography. Increased kurtosis of the tuber quantitative susceptibility mapping values was associated with epileptogenicity (P = .04 for the ictal group and P = .005 for the interictal group) by the generalized estimating equation model. Both groups had poor sensitivity (35.0% and 44.1%, respectively) but high specificity (94.6% and 78.6%, respectively). CONCLUSIONS: Our finding of increased kurtosis of quantitative susceptibility mapping values (heavy-tailed distribution) was highly specific, suggesting that it may be a useful biomarker to identify putative epileptogenic tubers in tuberous sclerosis complex. This finding motivates the investigation of underlying tuber mineralization and other properties driving kurtosis changes in quantitative susceptibility mapping values

Lesion detection in epilepsy surgery: Lessons from a prospective evaluation of a machine learning algorithm

AIM: To evaluate a lesion detection algorithm designed to detect focal cortical dysplasia (FCD) in children undergoing stereoelectroencephalography (SEEG) as part of their presurgical evaluation for drug-resistant epilepsy. METHOD: This was a prospective, single-arm, interventional study (Idea, Development, Exploration, Assessment, and Long-Term Follow-Up phase 1/2a). After routine SEEG planning, structural magnetic resonance imaging sequences were run through an FCD lesion detection algorithm to identify putative clusters. If the top three clusters were not already sampled, up to three additional SEEG electrodes were added. The primary outcome measure was the proportion of patients who had additional electrode contacts in the SEEG-defined seizure-onset zone (SOZ). RESULTS: Twenty patients (median age 12 years, range 4-18 years) were enrolled, one of whom did not undergo SEEG. Additional electrode contacts were part of the SOZ in 1 out of 19 patients while 3 out of 19 patients had clusters that were part of the SOZ but they were already implanted. A total of 16 additional electrodes were implanted in nine patients and there were no adverse events from the additional electrodes. INTERPRETATION: We demonstrate early-stage prospective clinical validation of a machine learning lesion detection algorithm used to aid the identification of the SOZ in children undergoing SEEG. We share key lessons learnt from this evaluation and emphasize the importance of robust prospective evaluation before routine clinical adoption of such algorithms

Diagnostic algorithm for children presenting with epilepsia partialis continua

Objective: To characterize a cohort of children with epilepsia partialis continua (EPC) and develop a diagnostic algorithm incorporating key differential diagnoses. / Methods: Children presenting with EPC to a tertiary pediatric neurology center between 2002 and 2019 were characterized. / Results: Fifty‐four children fulfilled EPC criteria. Median age at onset was 7 years (range 0.6‐15), with median follow‐up of 4.3 years (range 0.2‐16). The diagnosis was Rasmussen encephalitis (RE) in 30 of 54 (56%), a mitochondrial disorder in 12 of 54 (22.2%), and magnetic resonance imaging (MRI) lesion‐positive focal epilepsy in 6 of 54 (11.1%). No diagnosis was made in 5 of 54 (9%). Children with mitochondrial disorders developed EPC earlier; each additional year at presentation reduced the odds of a mitochondrial diagnosis by 26% (P = .02). Preceding developmental concerns (odds ratio [OR] 22, P < .001), no seizures prior to EPC (OR 22, P < .001), bilateral slowing on electroencephalogram (EEG) (OR 26, P < .001), and increased cerebrospinal fluid (CSF) protein level (OR 16) predicted a mitochondrial disorder. Asymmetry or hemiatrophy was evident on MRI at presentation with EPC in 18 of 30 (60%) children with RE, and in the remainder at a median of 6 months (range 3‐15) after EPC onset. The first diagnostic test is brain MRI. Hemiatrophy may permit a diagnosis of RE with unilateral clinical and EEG findings. For children in whom a diagnosis of RE cannot be made on first scan but the clinical and radiological presentation resembles RE, repeat imaging every 6 months is recommended to detect progressive unicortical hemiatrophy, and brain biopsy should be considered. Evidence of intrathecal inflammation (oligoclonal bands and raised neopterin) can be supportive. In children with bihemispheric EPC, rapid polymerase gamma testing is recommended and if negative, sequencing mtDNA and whole‐exome sequencing on blood‐derived DNA should be performed. / Significance: Children presenting with EPC due to a mitochondrial disorder show clinical features distinguishing them from RE and structural epilepsies. A diagnostic algorithm for children with EPC will allow targeted investigation and timely diagnosis

Clinical features, investigations, and outcomes of pediatric limbic encephalitis: A multicenter study

OBJECTIVES: To describe the clinical presentation, investigations, management, and disease course in pediatric autoimmune limbic encephalitis (LE). METHODS: In this retrospective observational study, from the UK Childhood Neuroinflammatory Disease network, we identified children from six tertiary centers with LE <18 years old between 2008 and 2021. Clinical and paraclinical data were retrieved from medical records. RESULTS: Twenty-five children fulfilling LE criteria were identified, with median age of 11 years (IQR 8, 14) and median follow-up of 24 months (IQR 18, 48). All children presented with seizures; 15/25 (60%) were admitted to intensive care. Neuroimaging demonstrated asymmetric mesial temporal changes in 8/25 (32%), and extra-limbic changes with claustrum involvement in 9/25 (38%). None were positive for LGI1/CASPR2 antibodies (Abs), 2/25 were positive for serum anti-NMDAR Abs, and 2/15 positive for anti-Hu Abs; one died from relapsing neuroblastoma. Two children had serum and CSF anti-GAD antibodies. Initial immune therapy included steroids in 23/25 (92%), intravenous immunoglobulin (IVIg) in 14/25 (56%), and plasma exchange in 7/25 (28%). The commonest second-line treatment was rituximab in 15/25 (60%). Median duration of hospital admission was 21 days (IQR 11, 30). At last follow-up, 13/25 (52%) had refractory seizures and 16/25 (64%) had memory impairment. Six children (24%) had modified Rankin Scale (mRS) scores ≥3. There was no significant difference in mRS, or long-term cognitive and epilepsy outcomes in those who received rituximab versus those who did not. INTERPRETATION: A diagnosis of autoimmune LE was associated with significant morbidity and adverse outcomes in this pediatric cohort

Clinical map document based on XML (cMDX): document architecture with mapping feature for reporting and analysing prostate cancer in radical prostatectomy specimens

<p>Abstract</p> <p>Background</p> <p>The pathology report of radical prostatectomy specimens plays an important role in clinical decisions and the prognostic evaluation in Prostate Cancer (PCa). The anatomical schema is a helpful tool to document PCa extension for clinical and research purposes. To achieve electronic documentation and analysis, an appropriate documentation model for anatomical schemas is needed. For this purpose we developed cMDX.</p> <p>Methods</p> <p>The document architecture of cMDX was designed according to Open Packaging Conventions by separating the whole data into template data and patient data. Analogue custom XML elements were considered to harmonize the graphical representation (e.g. tumour extension) with the textual data (e.g. histological patterns). The graphical documentation was based on the four-layer visualization model that forms the interaction between different custom XML elements. Sensible personal data were encrypted with a 256-bit cryptographic algorithm to avoid misuse. In order to assess the clinical value, we retrospectively analysed the tumour extension in 255 patients after radical prostatectomy.</p> <p>Results</p> <p>The pathology report with cMDX can represent pathological findings of the prostate in schematic styles. Such reports can be integrated into the hospital information system. "cMDX" documents can be converted into different data formats like text, graphics and PDF. Supplementary tools like cMDX Editor and an analyser tool were implemented. The graphical analysis of 255 prostatectomy specimens showed that PCa were mostly localized in the peripheral zone (Mean: 73% ± 25). 54% of PCa showed a multifocal growth pattern.</p> <p>Conclusions</p> <p>cMDX can be used for routine histopathological reporting of radical prostatectomy specimens and provide data for scientific analysis.</p

Genome-wide Investigation of multifocal and unifocal prostate cancer-are they Genetically different?

Prostate cancer is widely observed to be biologically heterogeneous. Its heterogeneity is manifested histologically as multifocal prostate cancer, which is observed more frequently than unifocal prostate cancer. The clinical and prognostic significance of either focal cancer type is not fu

Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures

Objective: We aimed to describe the extent of neurodevelopmental impairments andidentify the genetic etiologies in a large cohort of patients with epilepsy with myoclonicatonic seizures (MAE).Methods: We deeply phenotyped MAE patients for epilepsy features, intellectualdisability, autism spectrum disorder, and attention-deficit/hyperactivity disorderusing standardized neuropsychological instruments. We performed exome analysis(whole exome sequencing) filtered on epilepsy and neuropsychiatric gene sets toidentify genetic etiologies.Results: We analyzed 101 patients with MAE (70% male). The median age of seizureonset was 34 months (range = 6-72 months). The main seizure types were myoclonicatonic or atonic in 100%, generalized tonic-clonic in 72%, myoclonic in 69%, absencein 60%, and tonic seizures in 19% of patients. We observed intellectual disability in62% of patients, with extremely low adaptive behavioral scores in 69%. In addition,24% exhibited symptoms of autism and 37% exhibited attention-deficit/hyperactivitysymptoms. We discovered pathogenic variants in 12 (14%) of 85 patients, includingfive previously published patients. These were pathogenic genetic variants inSYNGAP1 (n = 3), KIAA2022 (n = 2), and SLC6A1 (n = 2), as well as KCNA2,SCN2A, STX1B, KCNB1, and MECP2 (n = 1 each). We also identified three newcandidate genes, ASH1L, CHD4, and SMARCA2 in one patient each.Significance: MAE is associated with significant neurodevelopmental impairment.MAE is genetically heterogeneous, and we identified a pathogenic genetic etiologyin 14% of this cohort by exome analysis. These findings suggest that MAE is a manifestationof several etiologies rather than a discrete syndromic entity