Pathogenic Somatic Variant in a Child With Tuberous Sclerosis Complex Without Pathogenic Variants in or .

Objective: To describe a child meeting diagnostic criteria for tuberous sclerosis complex (TSC) carrying a pathogenic somatic variant in , but no pathogenic variants in the 2 known TSC genes, or .

Methods: We present the clinical and imaging findings in a child presenting with drug-resistant focal seizures and multiple cortical tubers, a subependymal giant cell astrocytoma and multiple subependymal nodules in 1 cerebral hemisphere. Targeted panel sequencing and exome sequencing were performed on genomic DNA derived from blood and resected tuber tissue.

Basal ganglia dysplasia and mTORopathy: A potential cause of postoperative seizures in focal cortical dysplasia.

Pathogenic somatic MTOR variants in the cerebral cortex are a frequent cause of focal cortical dysplasia (FCD). We describe a child with drug and surgery-resistant focal epilepsy due to FCD type II who developed progressive enlargement and T2 signal hyperintensity in the ipsilateral caudate and lentiform nuclei. Histopathology of caudate nucleus biopsies showed dysmorphic neurons, similar to those in resected cortex.

Karawun: a software package for assisting evaluation of advances in multimodal imaging for neurosurgical planning and intraoperative neuronavigation.

Purpose: The neuroimaging research community-which includes a broad range of scientific, medical, statistical, and engineering disciplines-has developed many tools to advance our knowledge of brain structure, function, development, aging, and disease. Past research efforts have clearly shaped clinical practice. However, translation of new methodologies into clinical practice is challenging.

Assessment of intraoperative diffusion EPI distortion and its impact on estimation of supratentorial white matter tract positions in pediatric epilepsy surgery.

The effectiveness of correcting diffusion Echo Planar Imaging (EPI) distortion and its impact on tractography reconstruction have not been adequately investigated in the intraoperative MRI setting, particularly for High Angular Resolution Diffusion Imaging (HARDI) acquisition. In this study, we evaluated the effectiveness of EPI distortion correction using 27 legacy intraoperative HARDI datasets over two consecutive surgical time points, acquired without reverse phase-encoded data, from 17 children who underwent epilepsy surgery at our institution. The data was processed with EPI distortion correction using the Synb0-Disco technique (Schilling et al.

Intraoperative magnetic resonance imaging in epilepsy surgery: A systematic review and meta-analysis.

This systematic review investigated the added value of intraoperative magnetic resonance imaging (iMRI)-guidance in epilepsy surgery, compared to conventional non-iMRI surgery, with respect to the rate of gross total resection (GTR), postoperative seizure freedom, neurological deficits, non-neurological complications and reoperations. A comprehensive literature search was conducted using Medline, Embase, PubMed, and Cochrane Reviews databases. Randomized control trials, case control or cohort studies, and surgical case series published from January 1993 to February 2021 that reported on iMRI-guided epilepsy surgery outcomes for either adults or children were eligible for inclusion.

One-Stage, Limited-Resection Epilepsy Surgery for Bottom-of-Sulcus Dysplasia.

Objective: To determine whether 1-stage, limited corticectomy controls seizures in patients with MRI-positive, bottom-of-sulcus dysplasia (BOSD).

Methods: We reviewed clinical, neuroimaging, electrocorticography (ECoG), operative, and histopathology findings in consecutively operated patients with drug-resistant focal epilepsy and MRI-positive BOSD, all of whom underwent corticectomy guided by MRI and ECoG.

Results: Thirty-eight patients with a median age at surgery of 10.

Rationale, design, and methods of a randomized, controlled, open-label clinical trial with open-label extension to investigate the safety of vosoritide in infants, and young children with achondroplasia at risk of requiring cervicomedullary decompression surgery.

Achondroplasia causes narrowing of the foramen magnum and the spinal canal leading to increased mortality due to cervicomedullary compression in infants and significant morbidity due to spinal stenosis later in adulthood. Vosoritide is a C-natriuretic peptide analogue that has been shown to improve endochondral ossification in children with achondroplasia. The objective of this trial is to evaluate the safety of vosoritide and whether vosoritide can improve the growth of the foramen magnum and spinal canal in children that may require decompression surgery.

Cerebrospinal fluid liquid biopsy for detecting somatic mosaicism in brain.

Brain somatic mutations are an increasingly recognized cause of epilepsy, brain malformations and autism spectrum disorders and may be a hidden cause of other neurodevelopmental and neurodegenerative disorders. At present, brain mosaicism can be detected only in the rare situations of autopsy or brain biopsy. Liquid biopsy using cell-free DNA derived from cerebrospinal fluid has detected somatic mutations in malignant brain tumours.

Resection of tuber centers only for seizure control in tuberous sclerosis complex.

Our previous studies suggest the tuber center is the seizure focus in tuberous sclerosis complex (TSC). We report findings from 5 epilepsy surgeries in 4 children with TSC and focal motor seizures from single tubers in primary sensorimotor cortex in which resection was limited to the cortex in the tuber center. Intraoperative electrocorticography showed epileptiform activity in the tuber center, with or without propagation to the tuber rim and surrounding perituberal cortex.

Clinical seizure manifestations in the absence of synaptic connections.

We report a child with a history of temporal-parietal-occipital disconnection for epilepsy secondary to posterior quadrantic dysplasia who developed recurrent and prolonged bouts of distress and autonomic disturbance associated with EEG and PET evidence of status epilepticus confined to his disconnected cortex. These bouts were refractory to antiseizure medications but resolved following resection of the disconnected cortex. In the absence of synaptic connections, we hypothesise that his seizure-related symptoms were mediated either by neurochemical transmission in preserved vascular and lymphatic channels or by ephaptic transmission to trigeminal nerve fibres in overlying dura, producing symptoms akin to migraine.

Progress in neurosurgery: Contributions of women neurosurgeons in Asia and Australasia.

At the end of the first 100 years of neurosurgery as a specialty, it is appropriate to look back and then imagine the future. As neurosurgery celebrates its first century, the increasing role of women neurosurgeons is a major theme. This article documents the early women pioneers in neurosurgery in Asia and Australasia.

Gradient of brain mosaic RHEB variants causes a continuum of cortical dysplasia.

Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are related malformations with shared etiologies. We report three patients with a spectrum of cortical malformations associated with pathogenic brain-specific somatic Ras homolog enriched in brain (RHEB) variants. The somatic variant load directly correlated with the size of the malformation, with upregulated mTOR activity confirmed in dysplastic tissues.

Pediatric neurosurgery in Asia and Australasia: training and clinical practice.

Objective: There are limited data on the pediatric neurosurgical workforce in Asia and Australasia. The training and clinical practice of pediatric neurosurgeons need to be characterized in order to identify gaps in knowledge and skills, thereby establishing a framework from which to elevate pediatric neurosurgical care in the region.

Methods: An online survey for pediatric neurosurgeons was created in REDCap (Research Electronic Database Capture), collecting demographic information and data on pediatric neurosurgical training and clinical practice.

Genetic characterization identifies bottom-of-sulcus dysplasia as an mTORopathy.

Objective: To determine the genetic basis of bottom-of-sulcus dysplasia (BOSD), which is a highly focal and epileptogenic cortical malformation in which the imaging, electrophysiologic, and pathologic abnormalities are maximal at the bottom of sulcus, tapering to a normal gyral crown.

Methods: Targeted panel deep sequencing (>500×) was performed on paired blood and brain-derived genomic DNA from 20 operated patients with drug-resistant focal epilepsy and BOSD. Histopathology was assessed using immunohistochemistry.

Optic Radiation Tractography in Pediatric Brain Surgery Applications: A Reliability and Agreement Assessment of the Tractography Method.

Background: Optic radiation (OR) tractography may help predict and reduce post-neurosurgical visual field deficits. OR tractography methods currently lack pediatric and surgical focus.

Purpose: We propose a clinically feasible OR tractography strategy in a pediatric neurosurgery setting and examine its intra-rater and inter-rater reliability/agreements.

Second-hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA.

Focal cortical dysplasia (FCD) causes drug-resistant epilepsy and is associated with pathogenic variants in mTOR pathway genes. How germline variants cause these focal lesions is unclear, however a germline + somatic "2-hit" model is hypothesized. In a boy with drug-resistant epilepsy, FCD, and a germline DEPDC5 pathogenic variant, we show that a second-hit DEPDC5 variant is limited to dysmorphic neurons, and the somatic mutation load correlates with both dysmorphic neuron density and the epileptogenic zone.

Somatic mutation in the of Sturge-Weber syndrome.

Objective: To determine whether the R183Q mutation is present in the cases of Sturge-Weber syndrome (SWS) to establish a definitive molecular diagnosis.

Methods: We used sensitive droplet digital PCR (ddPCR) to detect and quantify the mutation in tissues from epilepsy surgery in 4 patients with leptomeningeal angiomatosis; none had ocular or cutaneous manifestations.

Results: Low levels of the mutation were detected in the brain tissue of all 4 cases-ranging from 0.

Potential delays in referral and assessment for epilepsy surgery in children with drug-resistant, early-onset epilepsy.

Objective: To study potential delays in epilepsy surgery in children with drug-resistant epilepsy (DRE) of early-onset.

Methods: Medical records were reviewed from 87 children with DRE and seizure onset before age 3 years who underwent epilepsy surgery between 2006 and 2015. Information was obtained about each child's epilepsy, treatment and specific time points in management.

A systematic evaluation of intraoperative white matter tract shift in pediatric epilepsy surgery using high-field MRI and probabilistic high angular resolution diffusion imaging tractography.

OBJECTIVE Characterization of intraoperative white matter tract (WMT) shift has the potential to compensate for neuronavigation inaccuracies using preoperative brain imaging. This study aimed to quantify and characterize intraoperative WMT shift from the global hemispheric to the regional tract-based scale and to investigate the impact of intraoperative factors (IOFs). METHODS High angular resolution diffusion imaging (HARDI) diffusion-weighted data were acquired over 5 consecutive perioperative time points (MR to MR) in 16 epilepsy patients (8 male; mean age 9.

Centre of epileptogenic tubers generate and propagate seizures in tuberous sclerosis.

SEE DUCHOWNY DOI101093/AWW216 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Multiple seizure foci, seizure propagation and epileptic spasms complicate presurgical seizure localization in tuberous sclerosis. Furthermore, controversy exists about the contribution of tubers, perituberal cortex and the underlying genetic abnormality to epileptogenesis. We aimed to determine the epileptogenic substrate in tuberous sclerosis by studying spatio-temporal patterns of seizure onset and propagation on intracranial EEG recordings in which multiple depth and surface electrodes sampled multiple tubers and perituberal cortex.

Ictal unilateral blinking is an unreliable lateralizing sign in tuberous sclerosis complex.

Objective: Ictal unilateral blinking is an uncommon but reportedly reliable lateralizing sign, indicating an ipsilateral seizure focus. We aimed to determine its lateralizing utility in patients with tuberous sclerosis complex (TSC).

Methods: We reviewed the video-EEGs of 92 children with TSC and drug-resistant epilepsy.

Automated alignment of perioperative MRI scans: A technical note and application in pediatric epilepsy surgery.

Conventional image registration utilizing brain voxel information may be erroneous in a neurosurgical setting due to pathology and surgery-related anatomical distortions. We report a novel application of an automated image registration procedure based on skull segmentation for magnetic resonance imaging (MRI) scans acquired before, during and after surgery (i.e.

Low rates of recurrence and slow progression of pediatric pilocytic astrocytoma after gross-total resection: justification for reducing surveillance imaging.

OBJECTIVE Pilocytic astrocytomas (PAs) are common brain tumors in children. Optimal management of PA is gross-total resection (GTR), after which event-free survival (EFS) is excellent. The tempo of recurrences, when they do occur, is relatively sparsely reported, and there is no agreed upon surveillance recommendation for patients in this category.

Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3.

We describe first cousin sibling pairs with focal epilepsy, one of each pair having focal cortical dysplasia (FCD) IIa. Linkage analysis and whole-exome sequencing identified a heterozygous germline frameshift mutation in the gene encoding nitrogen permease regulator-like 3 (NPRL3). NPRL3 is a component of GAP Activity Towards Rags 1, a negative regulator of the mammalian target of rapamycin complex 1 signaling pathway.