A multi-center comparison of surgical techniques for corpus Callosotomy in pediatric drug-resistant epilepsy.

OBJECTIVES: Corpus callosotomy (CC) is used to reduce seizures, primarily in patients with generalized drug-resistant epilepsy (DRE). The invasive nature of the procedure contributes to underutilization despite its potential superiority to other palliative procedures. The goal of this study was to use a multi-institutional epilepsy surgery database to characterize the use of CC across participating centers. METHODS: Data were acquired from the Pediatric Epilepsy Research Consortium (PERC) Surgery Database, a prospective observational study collecting data on children 0-18 years referred for surgical evaluation of DRE across 22 U.S. pediatric epilepsy centers. Patient, epilepsy, and surgical characteristics were collected across multiple CC modalities. Outcomes and complications were recorded and analyzed statistically. RESULTS: Eighty-three patients undergoing 85 CC procedures at 14 participating epilepsy centers met inclusion criteria. Mean age at seizure onset was 2.3 years (0-9.4); mean age for Phase I evaluation and surgical intervention were 9.45 (.1-20) and 10.46 (.2-20.6) years, respectively. Generalized seizure types were the most common (59%). Complete CC was performed in 88%. The majority of CC procedures (57%) were via open craniotomy, followed by laser interstitial thermal therapy (LiTT) (20%) and mini-craniotomy/endoscopic (mc/e) (22%). Mean operative times were significantly longer for LiTT, whereas mean estimated blood loss was greater in open cases. Complications occurred in 11 cases (13%) and differed significantly between surgical techniques (p < .001). There was no statistically significant difference in length of postoperative stay across approaches. Mean follow-up was 12.8 months (range 1-39). Favorable Engel outcomes were experienced by 37 (78.7%) of the patients who underwent craniotomy, 10 (58.8%) with LiTT, and 12 (63.2%) with mc/e; these differences were not statistically significant. SIGNIFICANCE: CC is an effective surgical modality for children with DRE. Regardless of surgical modality, complication rates are acceptable and seizure outcomes generally favorable. Newer, less-invasive, surgical approaches may lead to increased adoption of this efficacious therapeutic option for pediatric DRE.

Detection of tumor-derived cell-free DNA in cerebrospinal fluid using a clinically validated targeted sequencing panel for pediatric brain tumors.

PURPOSE: Clinical sequencing of tumor DNA is necessary to render an integrated diagnosis and select therapy for children with primary central nervous system (CNS) tumors, but neurosurgical biopsy is not without risk. In this study, we describe cell-free DNA (cfDNA) in blood and cerebrospinal fluid (CSF) as sources for "liquid biopsy" in pediatric brain tumors. METHODS: CSF samples were collected by lumbar puncture, ventriculostomy, or surgery from pediatric patients with CNS tumors. Following extraction, CSF-derived cfDNA was sequenced using UW-OncoPlex™, a clinically validated next-generation sequencing platform. CSF-derived cfDNA results and paired plasma and tumor samples concordance was also evaluated. RESULTS: Seventeen CSF samples were obtained from 15 pediatric patients with primary CNS tumors. Tumor types included medulloblastoma (n = 7), atypical teratoid/rhabdoid tumor (n = 2), diffuse midline glioma with H3 K27 alteration (n = 4), pilocytic astrocytoma (n = 1), and pleomorphic xanthoastrocytoma (n = 1). CSF-derived cfDNA was detected in 9/17 (53%) of samples, and sufficient for sequencing in 8/10 (80%) of extracted samples. All somatic mutations and copy-number variants were also detected in matched tumor tissue, and tumor-derived cfDNA was absent in plasma samples and controls. Tumor-derived cfDNA alterations were detected in the absence of cytological evidence of malignant cells in as little as 200 µl of CSF. Several clinically relevant alterations, including a KIAA1549::BRAF fusion were detected. CONCLUSIONS: Clinically relevant genomic alterations are detectable using CSF-derived cfDNA across a range of pediatric brain tumors. Next-generation sequencing platforms are capable of producing a high yield of DNA alterations with 100% concordance rate with tissue analysis.

Antibiotic impregnated catheters and intrathecal antibiotics for CSF shunt infection prevention in children undergoing low-risk CSF shunt surgery.

BACKGROUND: Cerebrospinal fluid (CSF) shunts allow children with hydrocephalus to survive and avoid brain injury (J Neurosurg 107:345-57, 2007; Childs Nerv Syst 12:192-9, 1996). The Hydrocephalus Clinical Research Network implemented non-randomized quality improvement protocols that were shown to decrease infection rates compared to pre-operative prophylactic intravenous antibiotics alone (standard care): initially with intrathecal (IT) antibiotics between 2007-2009 (J Neurosurg Pediatr 8:22-9, 2011), followed by antibiotic impregnated catheters (AIC) in 2012-2013 (J Neurosurg Pediatr 17:391-6, 2016). No large scale studies have compared infection prevention between the techniques in children. Our objectives were to compare the risk of infection following the use of IT antibiotics, AIC, and standard care during low-risk CSF shunt surgery (i.e., initial CSF shunt placement and revisions) in children. METHODS: A retrospective observational cohort study at 6 tertiary care children's hospitals was conducted using Pediatric Health Information System + (PHIS +) data augmented with manual chart review. The study population included children ≤ 18 years who underwent initial shunt placement between 01/2007 and 12/2012. Infection and subsequent CSF shunt surgery data were collected through 12/2015. Propensity score adjustment for regression analysis was developed based on site, procedure type, and year; surgeon was treated as a random effect. RESULTS: A total of 1723 children underwent initial shunt placement between 2007-2012, with 1371 subsequent shunt revisions and 138 shunt infections. Propensity adjusted regression demonstrated no statistically significant difference in odds of shunt infection between IT antibiotics (OR 1.22, 95% CI 0.82-1.81, p = 0.3) and AICs (OR 0.91, 95% CI 0.56-1.49, p = 0.7) compared to standard care. CONCLUSION: In a large, observational multicenter cohort, IT antibiotics and AICs do not confer a statistically significant risk reduction compared to standard care for pediatric patients undergoing low-risk (i.e., initial or revision) shunt surgeries.

Lower levels of Th1 and Th2 cytokines in cerebrospinal fluid (CSF) at the time of initial CSF shunt placement in children are associated with subsequent shunt revision surgeries.

OBJECTIVE: We compare cytokine profiles at the time of initial CSF shunt placement between children who required no subsequent shunt revision surgeries and children requiring repeated CSF shunt revision surgeries for CSF shunt failure. We also describe the cytokine profiles across surgical episodes for children who undergo multiple subsequent revision surgeries. METHODS: This pilot study was nested within an ongoing prospective multicenter study collecting CSF samples and clinical data at the time of CSF shunt surgeries since August 2014. We selected cases where CSF was available for children who underwent an initial CSF shunt placement and had no subsequent shunt revision surgeries during >=24 months of follow-up (n = 7); as well as children who underwent an initial CSF shunt placement and then required repeated CSF shunt revision surgeries (n = 3). Levels of 92 human cytokines were measured using the Olink immunoassay and 41 human cytokines were measured using Luminex based bead array on CSF obtained at the time of each child's initial CSF shunt placement and were displayed in heat maps. RESULTS: Qualitatively similar profiles for the majority of cytokines were observed among the patients in each group in both Olink and Luminex assays. Lower levels of MCP-3, CASP-8, CD5, CXCL9, CXCL11, eotaxin, IFN-γ, IL-13, IP-10, and OSM at the time of initial surgery were noted in the children who went on to require multiple surgeries. Pro- and anti-inflammatory cytokines were selected a priori and shown across subsequent revision surgeries for the 3 patients. Cytokine patterns differed between patients, but within a given patient pro-inflammatory and anti-inflammatory cytokines acted in a parallel fashion, with the exception of IL-4. CONCLUSIONS: Heat maps of cytokine levels at the time of initial CSF shunt placement for each child undergoing only a single initial CSF shunt placement and for each child undergoing repeat CSF shunt revision surgeries demonstrated qualitatively similar profiles for the majority of cytokines. Lower levels of MCP-3, CASP-8, CD5, CXCL9, CXCL11, eotaxin, IFN-γ, IL-13, IP-10, and OSM at the time of initial surgery were noted in the children who went on to require multiple surgeries. Better stratification by patient age, etiology, and mechanism of failure is needed to develop a deeper understanding of the mechanism of inflammation in the development of hydrocephalus and response to shunting in children.

Treatment of hydrocephalus following posterior fossa tumor resection: a multicenter collaboration from the Hydrocephalus Clinical Research Network.

OBJECTIVE: Persistent hydrocephalus following posterior fossa brain tumor (PFBT) resection is a common cause of morbidity in pediatric brain tumor patients, for which the optimal treatment is debated. The purpose of this study was to compare treatment outcomes between VPS and ETV in patients with persistent hydrocephalus following surgical resection of a PFBT. METHODS: A post-hoc analysis was performed of the Hydrocephalus Clinical Research Network (HCRN) prospective observational study evaluating VPS and ETV for pediatric patients. Children who experienced hydrocephalus secondary to PFBT from 2008 to 2021 were included. Primary outcomes were VPS/ETV treatment failure and time-to-failure (TTF). RESULTS: Among 241 patients, the VPS (183) and ETV (58) groups were similar in age, extent of tumor resection, and preoperative ETV Success Score. There was no difference in overall treatment failure between VPS and ETV (33.9% vs 31.0%, p = 0.751). However, mean TTF was shorter for ETV than VPS (0.45 years vs 1.30 years, p = 0.001). While major complication profiles were similar, compared to VPS, ETV patients had relatively higher incidence of minor CSF leak (10.3% vs. 1.1%, p = 0.003) and pseudomeningocele (12.1% vs 3.3%, p = 0.02). No ETV failures were identified beyond 3 years, while shunt failures occurred beyond 5 years. Shunt infections occurred in 5.5% of the VPS cohort. CONCLUSIONS: ETV and VPS offer similar overall success rates for PFBT-related postoperative hydrocephalus. ETV failure occurs earlier, while susceptibility to VPS failure persists beyond 5 years. Tumor histology and grade may be considered when selecting the optimal means of CSF diversion.

Profiling PI3K-AKT-MTOR variants in focal brain malformations reveals new insights for diagnostic care.

Focal malformations of cortical development including focal cortical dysplasia, hemimegalencephaly and megalencephaly, are a spectrum of neurodevelopmental disorders associated with brain overgrowth, cellular and architectural dysplasia, intractable epilepsy, autism and intellectual disability. Importantly, focal cortical dysplasia is the most common cause of focal intractable paediatric epilepsy. Gain and loss of function variants in the PI3K-AKT-MTOR pathway have been identified in this spectrum, with variable levels of mosaicism and tissue distribution. In this study, we performed deep molecular profiling of common PI3K-AKT-MTOR pathway variants in surgically resected tissues using droplet digital polymerase chain reaction (ddPCR), combined with analysis of key phenotype data. A total of 159 samples, including 124 brain tissue samples, were collected from 58 children with focal malformations of cortical development. We designed an ultra-sensitive and highly targeted molecular diagnostic panel using ddPCR for six mutational hotspots in three PI3K-AKT-MTOR pathway genes, namely PIK3CA (p.E542K, p.E545K, p.H1047R), AKT3 (p.E17K) and MTOR (p.S2215F, p.S2215Y). We quantified the level of mosaicism across all samples and correlated genotypes with key clinical, neuroimaging and histopathological data. Pathogenic variants were identified in 17 individuals, with an overall molecular solve rate of 29.31%. Variant allele fractions ranged from 0.14 to 22.67% across all mutation-positive samples. Our data show that pathogenic MTOR variants are mostly associated with focal cortical dysplasia, whereas pathogenic PIK3CA variants are more frequent in hemimegalencephaly. Further, the presence of one of these hotspot mutations correlated with earlier onset of epilepsy. However, levels of mosaicism did not correlate with the severity of the cortical malformation by neuroimaging or histopathology. Importantly, we could not identify these mutational hotspots in other types of surgically resected epileptic lesions (e.g. polymicrogyria or mesial temporal sclerosis) suggesting that PI3K-AKT-MTOR mutations are specifically causal in the focal cortical dysplasia-hemimegalencephaly spectrum. Finally, our data suggest that ultra-sensitive molecular profiling of the most common PI3K-AKT-MTOR mutations by targeted sequencing droplet digital polymerase chain reaction is an effective molecular approach for these disorders with a good diagnostic yield when paired with neuroimaging and histopathology.

A Comparison of Clinical Outcomes for Subependymal Giant Cell Astrocytomas Treated with Laser Interstitial Thermal Therapy, Open Surgical Resection, and mTOR Inhibitors.

INTRODUCTION: Subependymal giant cell astrocytoma (SEGA) is the most common CNS tumor in patients with tuberous sclerosis complex (TSC). Although these are benign, their proximity to the foramen of Monroe frequently causes obstructive hydrocephalus, a potentially fatal complication. Open surgical resection has been the mainstay of treatment; however, this can cause significant morbidity. The development of mTOR inhibitors has changed the treatment landscape, but there are limitations to their use. Laser interstitial thermal therapy (LITT) is an emerging treatment modality that has shown promise in treatment of a variety of intracranial lesions, including SEGAs. We present a single institution, retrospective study of patients treated for SEGAs with LITT, open resection, mTOR inhibitors, or a combination of these modalities. The primary study outcome was tumor volume at most recent follow-up compared with volume at treatment initiation. The secondary outcome was clinical complications associated with treatment modality. METHODS: Retrospective chart review was performed to identify patients with SEGAs treated at our institution from 2010 to 2021. Demographics, treatment information, and complications were collected from the medical record. Tumor volumes were calculated from imaging obtained at initiation of treatment and at most recent follow-up. Kruskal-Wallis nonparametric testing was used to assess differences in tumor volume and follow-up duration between groups. RESULTS: Four patients underwent LITT (3 with LITT only), three underwent open surgical resection, and four were treated with mTOR inhibitors only. Mean percent tumor volume reduction for each group was 48.6 ± 13.8, 90.7 ± 39.8, and 67.1 ± 17.2%, respectively. No statistically significant difference was identified comparing percent tumor volume reduction between the three groups (p = 0.0513). Additionally, there was no statistically significant difference in follow-up duration between groups (p = 0.223). Only 1 patient in our series required permanent CSF diversion and 4 discontinued or decreased the dose of mTOR inhibitor due to either cost or side effects. CONCLUSIONS: Our study suggests that LITT could be considered as a treatment option for SEGAs as it was effective in reducing tumor volume with very few complications. This modality is less invasive than open resection and may be an alternative for patients who are not candidates for mTOR inhibitors. We recommend an updated paradigm for SEGA treatment which includes LITT in select cases after consideration of patient-specific factors.

A clinically applicable functional MRI memory paradigm for use with pediatric patients.

OBJECTIVE: Clinically employable functional MRI (fMRI) memory paradigms are not yet established for pediatric patient epilepsy surgery workups. Seeking to establish such a paradigm, we evaluated the effectiveness of memory fMRI tasks we developed by quantifying individual activation in a clinical pediatric setting, analyzing patterns of activation relative to the side of temporal lobe (TL) pathology, and comparing fMRI and Wada test results. METHODS: We retrospectively identified 72 patients aged 6.7-20.9 years with pathology (seizure focus and/or tumor) limited to the TL who had attempted memory and language fMRI tasks over a 9-year period as part of presurgical workups. Memory fMRI tasks required visualization of autobiographical memories in a block design alternating with covert counting. Language fMRI protocols involved verb and sentence generation. Scans were both qualitatively interpreted and quantitatively assessed for blood oxygenation level dependent (BOLD) signal change using region of interest (ROI) masks. We calculated the percentage of successfully scanned individual cases, compared 2 memory task activation masks in cases with left versus right TL pathology, and compared fMRI with Wada tests when available. Patients who had viable fMRI and Wada tests had generally concordant results. RESULTS: Of the 72 cases, 60 (83%), aged 7.6-20.9 years, successfully performed the memory fMRI tasks and 12 (17%) failed. Eleven of 12 unsuccessful scans were due to motion and/or inability to perform the tasks, and the success of a twelfth was indeterminate due to orthodontic metal artifact. Seven of the successful 60 cases had distorted anatomy that precluded employing predetermined masks for quantitative analysis. Successful fMRI memory studies showed bilateral mesial temporal activation and quantitatively demonstrated: (1) left activation (L-ACT) less than right activation (R-ACT) in cases with left temporal lobe (L-TL) pathology, (2) nonsignificant R-ACT less than L-ACT in cases with right temporal lobe (R-TL) pathology, and (3) lower L-ACT plus R-ACT activation for cases with L-TL versus R-TL pathology. Patients who had viable fMRI and Wada tests had generally concordant results. SIGNIFICANCE: This study demonstrates evidence of an fMRI memory task paradigm that elicits reliable activation at the individual level and can generally be accomplished in clinically involved pediatric patients. This autobiographical memory paradigm showed activation in mesial TL structures, and cases with left compared to right TL pathology showed differences in activation consistent with extant literature in TL epilepsy. Further studies will be required to assess outcome prediction.

Robot-assisted stereoelectroencephalography in young children: technical challenges and considerations.

Robot-assisted stereoelectroencephalography (sEEG) is frequently employed to localize epileptogenic zones in patients with medically refractory epilepsy (MRE). Its methodology is well described in adults, but less so in children. Given the limited information available on pediatric applications, the objective is to describe the unique technical challenges and considerations of sEEG in the pediatric population. In this report, we describe our institutional experience with the technical aspects of robot-assisted sEEG in an exclusively pediatric epilepsy surgery unit, focusing on pre-, intra-, and post-operative nuances that are particular to the pediatric population. The pediatric population presents several unique challenges in sEEG, including reduced skull thickness relative to adults, incomplete neurologic development, and often special behavioral considerations. Pre-operative selection of putative epileptogenic zones requires careful multidisciplinary decision-making. Intraoperative attention to nuances in positioning, clamp selection, registration, and electrode placement are necessary. Activity considerations and electrode migration and removal are key post-operative considerations. Robot-assisted sEEG is a valuable tool in the armamentarium of techniques to characterize MRE. However, special considerations must be given to the pediatric population to optimize safety and efficacy.

Detection and Management of Tethered Cord in Anorectal Malformation: A Survey of Pediatric Neurosurgeons in the United States.

INTRODUCTION: The reported prevalence of tethered spinal cord in patients with anorectal malformations (ARMs) ranges from 9% to 64%. Practice patterns surrounding the diagnosis and management of tethered cord (TC) are suspected to vary, with consideration to the type of spine imaging, adjunct imaging modalities, what patients are offered surgical intervention, and how patients are followed after detethering. We sought to determine what consensus, if any, exists among pediatric neurosurgeons in the USA in terms of diagnosis and management of TC and, specifically, patients with TC and ARM. METHODS: A survey was sent to members of the American Society of Pediatric Neurosurgeons (ASPN). Members of the ASPN received an email with a link to an anonymous REDCap survey that asked about their experience with detethering procedures, indications for surgery, diagnostic tools used, and follow-up protocols. RESULTS: The survey was completed by 93 of the 192 ASPN members (48%). When respondents were asked about the total number of all simple filum detetherings they performed annually, 61% (N = 57) indicated they perform less than 10 for all TC patients. Ninety-three percent (N = 87) of neurosurgeons performed these procedures in patients with simple filum TC and ARM patients (TC + ARM) specifically. When asked about prophylactic detethering in those with a confirmed diagnosis of low-lying conus and with a filum fatty terminale, 59.1% (N = 55) indicated they would offer this to TC + ARM patients regardless of their age. Regarding preoperative workup for simple filum detethering, all respondents indicated they would order an MRI in both TC and TC + ARM patients, with a minority also requiring additional testing such as urodynamics, neurodevelopmental assessments, and anorectal manometry for both groups. When following patients postoperatively, almost all respondents indicated they would require clinical neurosurgical follow-up with a clinic visit (100% in all simple filum TC patients, 98.9% in fatty filum/low-lying conus TC + ARM patients), but there was wide variation in the use of other tools such as urological testing, neurodevelopmental assessment, and anorectal manometry. DISCUSSION/CONCLUSIONS: A wide variety of diagnostic criteria and indication for procedural intervention exists for management of TC patients with and without ARM. Further studies are needed to determine outcomes. Prospective protocols need to be developed and evaluated to standardize care for this patient population and determine best practices.

Pediatric hemispherectomy outcome: Adaptive functioning, intelligence, and memory.

OBJECTIVE: Our purpose was to characterize neuropsychological evaluation (NP) outcome following functional hemispherectomy in a large, representative cohort of pediatric patients. METHODS: We evaluated seizure and NP outcomes and medical variables for all post-hemispherectomy patients from Seattle Children's Hospital epilepsy surgery program between 1996 and 2020. Neuropsychological evaluation outcome tests used were not available on all patients due to the diversity of patient ages and competency that is typical of a representative pediatric cohort; all patients had at least an adaptive functioning or intelligence measure, and a subgroup had memory testing. RESULTS: A total of 71 hemispherectomy patients (37 right; 34 females) yielded 66 with both preoperative (PREOP) plus postoperative (POSTOP) NPs and 5 with POSTOP only. Median surgery age was 5.7 (IQR 2-9.9) years. Engel classification indicated excellent seizure outcomes: 59 (84%) Class I, 6 (8%) Class II, 5 (7%) Class III, and 1 (1%) Class IV. Medical variables - including seizure etiology, surgery age, side, presurgical seizure duration, unilateral or bilateral structural abnormalities, secondarily generalized motor seizures - were not associated with either Engel class or POSTOP NP scores, though considerable heterogeneity was evident. Median PREOP and POSTOP adaptive functioning (PREOP n = 45, POSTOP n = 48) and intelligence (PREOP n = 29, POSTOP n = 36) summary scores were exceptionally low and did not reveal group decline from PREOP to POSTOP. Fifty-five of 66 (85%) cases showed stability or improvement. Specifically, 5 (8%) improved; 50 (76%) showed stability; and 11 (16%) declined. Improve and decline groups showed clinically interesting, but not statistical, differences in seizure control and age. Median memory summary scores were low and also showed considerable heterogeneity. Overall median PREOP to POSTOP memory scores (PREOP n = 16, POSTOP n = 24) did not reveal declines, and verbal memory scores improved. Twenty six percent of intelligence and 33% of memory tests had verbal versus visual-spatial discrepancies; all but one favored verbal, regardless of hemispherectomy side. SIGNIFICANCE: This large, single institution study revealed excellent seizure outcome in 91% of all 71 patients plus stability and/or improvement of intelligence and adaptive functioning in 85% of 66 patients who had PREOP plus POSTOP NPs. Memory was similarly stable overall, and verbal memory improved. Medical variables did not predict group NP outcomes though heterogeneity argues for further research. This study is unique for cohort size, intelligence plus memory testing, and evidence of primacy of verbal over visual-spatial development, despite hemispherectomy side. This study reinforces the role of hemispherectomy in achieving good seizure outcome while preserving functioning.

Issues of consent and assent in pediatric neurosurgery.

BACKGROUND: Consent and assent are important concepts to understand in the care of pediatric neurosurgery patients. Recently it has been recommended that although pediatric patients generally do not have the legal capacity to make medical decisions, they be encouraged to be involved in their own care. Given the paucity of information on this topic in the neurosurgery community, the objective is to provide pediatric neurosurgeons with recommendations on how to involve their patients in medical decision-making. METHODS: We review the essential elements and current guidelines of consent and assent for pediatric patients using illustrative neurosurgical case vignettes. RESULTS: The pediatric population ranges widely in cognitive and psychological development making the process of consent and assent quite complex. The role of the child or adolescent in medical decision-making, issues associated with obtaining assent or dissent, and informed refusal of treatment are considered. CONCLUSION: The process of obtaining consent and assent represents a critical yet often overlooked aspect to care of pediatric neurosurgical patients. The pediatric neurosurgeon must be able to distill immensely complex and high-risk procedures into simple, understandable terms. Furthermore, they must recognize when the child's dissent or refusal to treatment is acceptable. In general, allowing children to be involved in their neurosurgical care is empowering and gives them both identity and agency, which is the vital first step to a successful neurosurgical intervention.

Hydrocephalus treatment in patients with craniosynostosis: an analysis from the Hydrocephalus Clinical Research Network prospective registry.

OBJECTIVE: Hydrocephalus may be seen in patients with multisuture craniosynostosis and, less commonly, single-suture craniosynostosis. The optimal treatment for hydrocephalus in this population is unknown. In this study, the authors aimed to evaluate the success rate of ventriculoperitoneal shunt (VPS) treatment and endoscopic third ventriculostomy (ETV) both with and without choroid plexus cauterization (CPC) in patients with craniosynostosis. METHODS: Utilizing the Hydrocephalus Clinical Research Network (HCRN) Core Data Project (Registry), the authors identified all patients who underwent treatment for hydrocephalus associated with craniosynostosis. Descriptive statistics, demographics, and surgical outcomes were evaluated. RESULTS: In total, 42 patients underwent treatment for hydrocephalus associated with craniosynostosis. The median gestational age at birth was 39.0 weeks (IQR 38.0, 40.0); 55% were female and 60% were White. The median age at first craniosynostosis surgery was 0.6 years (IQR 0.3, 1.7), and at the first permanent hydrocephalus surgery it was 1.2 years (IQR 0.5, 2.5). Thirty-three patients (79%) had multiple different sutures fused, and 9 had a single suture: 3 unicoronal (7%), 3 sagittal (7%), 2 lambdoidal (5%), and 1 unknown (2%). Syndromes were identified in 38 patients (90%), with Crouzon syndrome being the most common (n = 16, 42%). Ten patients (28%) received permanent hydrocephalus surgery before the first craniosynostosis surgery. Twenty-eight patients (67%) underwent VPS treatment, with the remaining 14 (33%) undergoing ETV with or without CPC (ETV ± CPC). Within 12 months after initial hydrocephalus intervention, 14 patients (34%) required revision (8 VPS and 6 ETV ± CPC). At the most recent follow-up, 21 patients (50%) required a revision. The revision rate decreased as age increased. The overall infection rate was 5% (VPS 7%, 0% ETV ± CPC). CONCLUSIONS: This is the largest prospective study reported on children with craniosynostosis and hydrocephalus. Hydrocephalus in children with craniosynostosis most commonly occurs in syndromic patients and multisuture fusion. It is treated at varying ages; however, most patients undergo surgery for craniosynostosis prior to hydrocephalus treatment. While VPS treatment is performed more frequently, VPS and ETV are both reasonable options, with decreasing revision rates with increasing age, for the treatment of hydrocephalus associated with craniosynostosis.

Children with DIPG and high-grade glioma treated with temozolomide, irinotecan, and bevacizumab: the Seattle Children's Hospital experience.

INTRODUCTION: Beyond focal radiation, there is no consensus standard therapy for pediatric high-grade glioma (pHGG) and outcomes remain dismal. We describe the largest molecularly-characterized cohort of children with pHGG treated with a 3-drug maintenance regimen of temozolomide, irinotecan, and bevacizumab (TIB) following radiation. METHODS: We retrospectively reviewed 36 pediatric patients treated with TIB at Seattle Children's Hospital from 2009 to 2018 and analyzed survival using the Kaplan-Meier method. Molecular profiling was performed by targeted DNA sequencing and toxicities, steroid use, and palliative care utilization were evaluated. RESULTS: Median age at diagnosis was 10.9 years (18 months-18 years). Genetic alterations were detected in 26 genes and aligned with recognized molecular subgroups including H3 K27M-mutant (12), H3F3A G34-mutant (2), IDH-mutant (4), and hypermutator profiles (4). Fifteen patients (42%) completed 12 planned cycles of maintenance. Side effects associated with chemotherapy delays or modifications included thrombocytopenia (28%) and nausea/vomiting (19%), with temozolomide dosing most frequently modified. Median event-free survival (EFS) and overall survival (OS) was 16.2 and 20.1 months, with shorter survival seen in DIPG (9.3 and 13.3 months, respectively). Survival at 1, 2, and 5 years was 80%, 10% and 0% for DIPG and 85%, 38%, and 16% for other pHGG. CONCLUSION: Our single-center experience demonstrates tolerability of this 3-drug regimen, with prolonged survival in DIPG compared to historical single-agent temozolomide. pHGG survival was comparable to analogous 3-drug regimens and superior to historical agents; however, cure was rare. Children with pHGG remain excellent candidates for the study of novel therapeutics combined with standard therapy.

Structural MRI and tract-based spatial statistical analysis of diffusion tensor imaging in children with hemimegalencephaly.

PURPOSE: To investigate the gross white matter abnormalities in the structural brain MR imaging as well as white matter microstructural alterations using tract-based spatial statistics (TBSS) analysis of diffusion tensor imaging (DTI) in both affected and contralateral cerebral hemispheres of children with hemimegalencephaly (HMEG). METHODS: From 2003 to 2019, we retrospectively reviewed brain MR images in 20 children (11 boys, 2 days-16.5 years) with HMEG, focusing on gross white matter abnormalities. DTI was evaluated in 12 patients (8 boys, 3 months-16.5 years) with HMEG and 12 age-, sex-, and magnetic field strength-matched control subjects. TBSS analysis was performed to analyze main white matter tracts. Regions of significant differences in fractional anisotropy (FA) were determined between HMEG and control subjects and between affected and contralateral hemispheres of HMEG. RESULTS: Gross white matter abnormalities were noted in both affected (n = 20, 100%) and contralateral hemisphere (n = 4, 20%) of HMEG. FA values were significantly decreased in both hemispheres of HMEG, compared with control subjects (P < 0.05). Contralateral hemispheres of HMEG showed regions with significantly decreased FA values compared with affected hemispheres (P < 0.05). CONCLUSIONS: In addition to gross white matter abnormalities particularly evident in affected hemispheres, DTI analysis detected widespread microstructural alterations in both affected and contralateral hemispheres in HMEG suggesting HMEG may involve broader abnormalities in neuronal networks.

Medicolegal issues in abusive head trauma for the pediatric neurosurgeon.

The purpose of this article is to serve as a rational guide for the pediatric neurosurgeon in navigating common medicolegal issues that arise in the management of abusive head trauma (AHT). Many of these issues may be unfamiliar or unpleasant to surgeons focused on addressing disease. The authors begin with a brief history on the origins of the diagnosis of AHT and the controversy surrounding it, highlighting some of the facets of the diagnosis that make it particularly unique in pediatric neurosurgery. They then review some special medical considerations in these patients through the perspective of the neurosurgeon and provide several examples as illustration. The authors discuss how to appropriately document these cases in the medical record for expected legal review, and last, they provide an overview of the legal process through which the neurosurgeon may be called to provide testimony.

Progress in diffuse intrinsic pontine glioma: advocating for stereotactic biopsy in the standard of care.

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brainstem tumor affecting approximately 300 children in the US annually. Median survival is less than 1 year, and radiation therapy has been the mainstay of treatment for decades. Recent advances in the biological understanding of the disease have identified the H3K27M mutation in nearly 80% of DIPGs, leading to the 2016 WHO classification of diffuse midline glioma H3K27M-mutant, a grade IV brainstem tumor. Developments in epigenetic targeting of transcriptional tendencies have yielded potential molecular targets for clinical trials. Chimeric antigen receptor T cell therapy has also shown preclinical promise. Recent clinical studies, including prospective trials, have demonstrated the safety and feasibility of pediatric brainstem biopsy in the setting of DIPG and other brainstem tumors. Given developments in the ability to analyze DIPG tumor tissue to deepen biological understanding of this disease and develop new therapies for treatment, together with the increased safety of stereotactic brainstem biopsy, the authors present a case for offering biopsy to all children with suspected DIPG. They also present their standard operative techniques for image-guided, frameless stereotactic biopsy.

Pediatric functional hemispherectomy: operative techniques and complication avoidance.

Functional hemispherectomy/hemispherotomy is a disconnection procedure for severe medically refractory epilepsy where the seizure foci diffusely localize to one hemisphere. It is an improvement on anatomical hemispherectomy and was first performed by Rasmussen in 1974. Less invasive surgical approaches and refinements have been made to improve seizure freedom and minimize surgical morbidity and complications. Key anatomical structures that are disconnected include the 1) internal capsule and corona radiata, 2) mesial temporal structures, 3) insula, 4) corpus callosum, 5) parietooccipital connection, and 6) frontobasal connection. A stepwise approach is indicated to ensure adequate disconnection and prevent seizure persistence or recurrence. In young pediatric patients, careful patient selection and modern surgical techniques have resulted in > 80% seizure freedom and very good functional outcome. In this report, the authors summarize the history of hemispherectomy and its development and present a graphical guide for this anatomically challenging procedure. The use of the osteoplastic flap to improve outcome and the management of hydrocephalus are discussed.

Laser interstitial thermal therapy for pediatric atypical teratoid/rhabdoid tumor: case report.

Herein, the authors describe the successful use of laser interstitial thermal therapy (LITT) for management of metastatic craniospinal disease for biopsy-proven atypical teratoid/rhabdoid tumor in a 16-month-old boy presenting to their care. Specifically, LITT was administered to lesions of the right insula and left caudate. The patient tolerated 2 stages of LITT to the aforementioned lesions without complication and with evidence of radiographic improvement of lesions at the 2- and 6-month follow-up appointments. To the authors' knowledge, this represents the first such published report of LITT for management of atypical teratoid/rhabdoid tumor.

Awake Mapping of the Auditory Cortex during Tumor Resection in an Aspiring Musical Performer: A Case Report.

INTRODUCTION: Preoperative functional MRI (fMRI) and intraoperative awake cortical mapping are established strategies to identify and preserve critical language structures during neurosurgery. There is growing appreciation for the need to similarly identify and preserve eloquent tissue critical for music production. CASE REPORT: A 19-year-old female musician, with a 3- to 4-year history of events concerning for musicogenic seizures, was found to have a right posterior temporal tumor, concerning for a low-grade glial neoplasm. Preoperative fMRI assessing passive and active musical tasks localized areas of activation directly adjacent to the tumor margin. Cortical stimulation during various musical tasks did not identify eloquent tissue near the surgical site. A gross total tumor resection was achieved without disruption of singing ability. At 9-month follow-up, the patient continued to have preserved musical ability with full resolution of seizures and without evidence of residual lesion or recurrence. CONCLUSION: A novel strategy for performing an awake craniotomy, incorporating preoperative fMRI data for music processing with intraoperative cortical stimulation, interpreted with the assistance of a musician expert and facilitated gross total resection of the patient's tumor without comprising her musical abilities.