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Imaging plays a fundamental role in the managing childhood neurologic, neurosurgical and neuro-oncological disease. Employing multi-parametric MRI techniques, such as spectroscopy and diffusion- and perfusion-weighted imaging, to the radiophenotyping of neuroradiologic conditions is becoming increasingly prevalent, particularly with radiogenomic analyses correlating imaging characteristics with molecular biomarkers of disease. However, integration into routine clinical practice remains elusive. With modern multi-parametric MRI now providing additional data beyond anatomy, informing on histology, biology and physiology, such metric-rich information can present as information overload to the treating radiologist and, as such, information relevant to an individual case can become lost. Artificial intelligence techniques are capable of modelling the vast radiologic, biological and clinical datasets that accompany childhood neurologic disease, such that this information can become incorporated in upfront prognostic modelling systems, with artificial intelligence techniques providing a plausible approach to this solution. This review examines machine learning approaches than can be used to underpin such artificial intelligence applications, with exemplars for each machine learning approach from the world literature. Then, within the specific use case of paediatric neuro-oncology, we examine the potential future contribution for such artificial intelligence machine learning techniques to offer solutions for patient care in the form of decision support systems, potentially enabling personalised medicine within this domain of paediatric radiologic practice.

Unexplained or idiopathic pituitary stalk thickening or central diabetes insipidus not only harbours rare occult malignancies in 40% of cases but can also reflect benign congenital defects. Between 2014 and 2019, a multidisciplinary, expert national guideline development group in the UK systematically developed a management flowchart and clinical practice guideline to inform specialist care and improve outcomes in children and young people (aged

Ependymoma (EPN) is the second most common malignant paediatric brain tumour with a five-year survival rate of only 25% following relapse. While molecular heterogeneity between EPN tumours is well understood, little is known concerning spatially-distinct intratumour heterogeneity within patients. In this context, we present a multi-omics integration of expression data at transcriptomic and metabolomic levels revealing intratumour heterogeneity and novel therapeutic targets. Surgically resected ependymoma tissue from two epigenetic subgroups, posterior fossa-A (PF-A) and supratentorial RELA, were first homogenised and polar metabolites, lipids and RNA simultaneously extracted from the same cellular population. Using liquid chromatography-mass spectrometry (LC-MS) and RNAseq 115 metabolites and 1580 upregulated genes were identified between the two subgroups, therefore validating previously reported genetic clustering of these two subtypes. Sampling of anatomically distinct regions was performed between eight PF-A EPN patients and multi-omic data was compared across 28 intratumour regions, with at least 3 different regions per patient. Integration of genes and metabolites revealed 124 dysregulated metabolic pathways, encompassing 156 genes and 49 metabolites. A large number of interactions occur in the gluconeogenesis and glycine pathways in 6 out of 8 patients, putatively representing therapeutically relevant ubiquitous metabolic pathways critical for EPN survival. Each anatomical region also presented at least one unique gene-metabolite interaction demonstrating heterogeneity within and across PF-A EPN tumours. A subset of the eight most prevalent genes across patients (GAD1, NT5C, FBP1, FMO3, HK3, TALDO1, NT5E, ALDH3A1) were selected for in vitro metabolic assays using 10 repurposed cytotoxic agents against PF-A EPN cell lines derived from intratumour regions of the same patient. 5/8 genes map within the gluconeogenesis metabolic pathway, further highlighting its significance within PF-A EPN. This is the first instance where multi-omic data integration and intratumour heterogeneity has been investigated for paediatric EPN revealing novel potential targets in the context of gene-metabolite correlations.

Summary Background The CNS manifestations of COVID-19 in children have primarily been described in case reports, which limit the ability to appreciate the full spectrum of the disease in paediatric patients. We aimed to identify enough cases that could be evaluated in aggregate to better understand the neuroimaging manifestations of COVID-19 in the paediatric population. Methods An international call for cases of children with encephalopathy related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and abnormal neuroimaging findings was made. Clinical history and associated plasma and cerebrospinal fluid data were requested. These data were reviewed by a central neuroradiology panel, a child neurologist, and a paediatric infectious diseases expert. The children were categorised on the basis of their time of probable exposure to SARS-CoV-2. In addition, cases were excluded when a direct link to SARS-CoV-2 infection could not be established or an established alternate diagnostic cause could be hypothesised. The accepted referral centre imaging data, from ten countries, were remotely reviewed by a central panel of five paediatric neuroradiologists and a consensus opinion obtained on the imaging findings. Findings 38 children with neurological disease related to SARS-CoV-2 infection were identified from France (n=13), the UK (n=8), the USA (n=5), Brazil (n=4), Argentina (n=4), India (n=2), Peru (n=1), and Saudi Arabia (n=1). Recurring patterns of disease were identified, with neuroimaging abnormalities ranging from mild to severe. The most common imaging patterns were postinfectious immune-mediated acute disseminated encephalomyelitis-like changes of the brain (16 patients), myelitis (eight patients), and neural enhancement (13 patients). Cranial nerve enhancement could occur in the absence of corresponding neurological symptoms. Splenial lesions (seven patients) and myositis (four patients) were predominantly observed in children with multisystem inflammatory syndrome. Cerebrovascular complications in children were less common than in adults. Significant pre-existing conditions were absent and most children had favourable outcomes. However, fatal atypical CNS co-infections developed in four previously healthy children infected with SARS-CoV-2. Interpretation Acute-phase and delayed-phase SARS-CoV-2-related CNS abnormalities are seen in children. Recurring patterns of disease and atypical neuroimaging manifestations can be found and should be recognised being as potentially due to SARS-CoV-2 infection as an underlying aetiological factor. Studies of paediatric specific cohorts are needed to better understand the effects of SARS-CoV-2 infection on the CNS at presentation and on long-term follow-up in children. Funding American Society of Pediatric Neuroradiology, University of Manchester (Manchester, UK). Video Abstract Neuroimaging manifestations in children with SARS-CoV-2 infection

Purpose To evaluate overall survival for atypical teratoid rhabdoid tumors (ATRTs) in relation to extent of surgical resection. Methods The neurosurgical tumor databases from three UK Pediatric centers (University Hospital of Wales, Alder Hey and Royal Manchester Children’s Hospital) were analyzed. Patients with a diagnosis of ATRT were identified between 2000 and 2018. Data was collected regarding demographics, extent of resection, complications, and overall survival. Results Twenty-four patients diagnosed with ATRT underwent thirty-eight operations. The age range was 20 days to 147 months (median 17.5 months). The most common location for the tumor was the posterior fossa (nine patients; 38%). Six patients (25%) underwent a complete total resection (CTR), seven (29%) underwent a near total resection (NTR), eight (33.3%) underwent a subtotal resection (STR), and three patients (12.5%) had biopsy only. Two-thirds of patients who underwent a CTR are still alive, as of March 2019, compared to 29% in the NTR and 12.5% in the STR groups. Out of the thirty-eight operations, there were a total of twenty-two complications, of which the most common was pseudomeningocele (27%). The extent of surgical resection (p = 0.021), age at surgery (p = 0.00015), and the presence of metastases at diagnosis (0.015) significantly affected overall survival. Conclusions Although these patients are a highly vulnerable group, maximal resection is recommended where possible, for the best chance of long-term survival. However, near total resections are likely beneficial when compared with subtotal resections and biopsy alone. Maximal surgical resection should be combined with adjuvant therapies for the best long-term outcomes.

Aims: Resident and peripherally derived glioma associated microglia/macrophages (GAMM) play a key role in driving tumour progression, angiogenesis, invasion and attenuating host immune responses. Differentiating these cells’ origins is challenging and current preclinical models such as irradiation-based adoptive transfer, parabiosis and transgenic mice have limitations. We aimed to develop a novel nonmyeloablative transplan- tation (NMT) mouse model that permits high levels of peripheral chimerism without blood-brain barrier (BBB) damage or brain infiltration prior to tumour implantation. Methods: NMT dosing was determined in C57BL/6J or Pep3/CD45.1 mice conditioned with concentrations of busulfan ranging from 25 mg/kg to 125 mg/kg. Donor haematopoietic cells labelled with eGFP or CD45.2 were injected via tail vein. Donor chimerism was measured in peripheral blood, bone marrow and spleen using flow cytometry. BBB integrity was assessed with anti-IgG and anti-fibrinogen antibodies. Immuno-competent chimerised animals were orthotopically implanted with murine glioma GL-261 cells. Central and peripheral cell contributions were assessed using mimmunohistochemistry and flow cytometry. GAMM subpopulation analysis of peripheral cells was performed using Ly6C/MHCII/MerTK/CD64. Results: NMT achieves >80% haematopoietic chimerism by 12 weekswithout BBB damage and normal life span. Bone marrow derived cells (BMDC) and peripheral macrophages accounted for approximately 45% of the GAMM population in GL-261 implanted tumours. Existing markers such as CD45 high/low proved inaccurate to determine central and peripheral populations while Ly6C/MHCII/MerTK/CD64 reliably differentiated GAMM subpopulations in chimerised and unchimerised mice. Conclusion: NMT is a powerful method for dissecting tumour microglia and macrophage subpopulations and can guide further investigation of BMDC subsets in glioma and neuro-inflammatory diseases.

Object Endoscopic third ventriculostomy (ETV) uses anatomical spaces of the ventricular system to reach the third ventricle floor and create an alternative pathway for cerebrospinal fluid flow. Optimal ETV trajectories have been previously proposed in the literature, designed to grant access to the third ventricle floor without a displacement of eloquent periventricular structures. However, in hydrocephalus, there is a significant variability to the configuration of the ventricular system, implying that the optimal ETV trajectory and cranial entry point needs to be planned on a case-by-case basis. In the current study, we created a mathematical model, which tailors the optimal ETV entry point to the individual case by incorporating the ventricle dimensions. Methods We retrospectively reviewed the imaging of 30 consecutive pediatric patients with varying degrees of ventriculomegaly. Three dimensional radioanatomical models were created using preoperative MRI scans to simulate the optimal ETV trajectory and entry point for each case. The surface location of cranial entry points for individual ETV trajectories was recorded as Cartesian coordinates centered at Bregma. The distance from the Bregma in the coronal plane represented as “x”, and the distance from the coronal suture in the sagittal plane represented as “y”. The correlation between the ventricle dimensions and the x, y coordinates were tested using linear regression models. Results The distance of the optimal ETV entry point from the Bregma in the coronal plane (“x”) and from the coronal suture in the sagittal plane (“y”) correlated well with the frontal horn ratio (FHR). The coordinates for x and y were fitted along the following linear equations: x = 85.8 FHR−13.3 (r 2 = 0.84, p

Objectives Aqueduct stenosis (AS) and fourth ventricle outflow obstruction are rare associations of neurofibromatosis type 1 (NF1), resulting in ventriculomegaly and hydrocephalus requiring surgical treatment. This study aims to identify the prevalence of AS and its patterns of clinical presentation, aetiology and treatment in the paediatric complex NF1 population. Patients and methods Patients with NF-1 aged 0-18 years were recruited from the Regional Genetic Family Register, following institutional review board approval. Magnetic resonance imaging data and clinical documents were reviewed with respect to clinical presentation, degree of ventriculomegaly, aetiological factors and management of AS and fourth ventricle outflow obstruction. Results 24 of the 233 paediatric patients seen within the NHS highly specialised service for complex NF1 were found to have AS or and fourth ventricle outflow obstruction. This included 13 males and 11 females with a mean age of 9 years 5 months (range 8 months - 17 years). The majority of patients with AS or fourth ventricle outflow obstruction presented with symptoms of raised intracranial pressure associated with ventriculomegaly and/or hydrocephalus (n = 18). However, in 25 % of patients, AS was an incidental finding on MRI and was observed both in the presence (n = 2) and absence (n = 4) of ventriculomegaly. In the majority of cases a single cause of AS was identified (n = 16), of which tectal plate thickening (n = 7) was most frequently observed. The remaining 8 patients had multiple causes of AS, in which tectal plate thickening (n = 7) and aqueductal webs (n = 5) were the most common observations. Surgery was performed on all patients with evidence of raised pressure (n = 8) by performing endoscopic third ventriculostomy (ETV) (n = 5) or ventriculoperitoneal (VP)-shunting (n = 3). Tectal plate thickening was most frequently observed in patients who underwent ETV (n = 3), followed by aqueductal web (n = 1) and T2-signal changes in the tectal plate (n = 1). Patients treated with VP-shunt had 4th ventricle outflow obstruction (n = 2) and a tectal plate tumour (n = 1). Conclusion This study identifies that AS is more prevalent amongst the paediatric complex NF-1 population than previously reported, occurring in 10 % of cases. Our findings demonstrate that AS is most commonly symptomatic in presentation but can be asymptomatic in 25 % of paediatric complex NF1 patients. In this population, AS can occur both in the presence and absence of ventriculomegaly and therefore requires careful monitoring for development of hydrocephalus. In this study, over one third of patients (9 of 24 patients) with AS eventually required treatment.

Background Chimeric mouse models generated via adoptive bone marrow transfer are the foundation for immune cell tracking in neuroinflammation. Chimeras that exhibit low chimerism levels, blood-brain barrier disruption and pro-inflammatory effects prior to the progression of the pathological phenotype, make it difficult to distinguish the role of immune cells in neuroinflammatory conditions. Head-shielded irradiation overcomes many of the issues described and replaces the recipient bone marrow system with donor haematopoietic cells expressing a reporter gene or different pan-leukocyte antigen, whilst leaving the blood-brain barrier intact. However, our previous work with full body irradiation suggests that this may generate a pro-inflammatory peripheral environment which could impact on the brain’s immune microenvironment. Our aim was to compare non-myeloablative busulfan conditioning against head-shielded irradiation bone marrow chimeras prior to implantation of glioblastoma, a malignant brain tumour with a pro-inflammatory phenotype. Methods Recipient wild-type/CD45.1 mice received non-myeloablative busulfan conditioning (25 mg/kg), full intensity head-shielded irradiation, full intensity busulfan conditioning (125 mg/kg) prior to transplant with whole bone marrow from CD45.2 donors and were compared against untransplanted controls. Half the mice from each group were orthotopically implanted with syngeneic GL-261 glioblastoma cells. We assessed peripheral blood, bone marrow and spleen chimerism, multi-organ pro-inflammatory cytokine profiles at 12 weeks and brain chimerism and immune cell infiltration by whole brain flow cytometry before and after implantation of glioblastoma at 12 and 14 weeks respectively. Results Both non-myeloablative conditioning and head-shielded irradiation achieve equivalent blood and spleen chimerism of approximately 80%, although bone marrow engraftment is higher in the head-shielded irradiation group and highest in the fully conditioned group. Head-shielded irradiation stimulated pro-inflammatory cytokines in the blood and spleen but not in the brain, suggesting a systemic response to irradiation, whilst non-myeloablative conditioning showed no cytokine elevation. Non-myeloablative conditioning achieved higher donor chimerism in the brain after glioblastoma implantation than head-shielded irradiation with an altered immune cell profile. Conclusion Our data suggest that non-myeloablative conditioning generates a more homeostatic peripheral inflammatory environment than head-shielded irradiation to allow a more consistent evaluation of immune cells in glioblastoma and can be used to investigate the roles of peripheral immune cells and bone marrow-derived subsets in other neurological diseases. Electronic supplementary material The online version of this article (10.1186/s12974-019-1410-y) contains supplementary material, which is available to authorized users.

Paediatric Ependymoma is the second most common malignant brain tumour of childhood with approximately 50% of cases recurring. It has been described as a “surgical” disease since patients who have undergone a gross total surgical resection (GTR) have a better prognosis than those who have a subtotal resection (STR). Analysis of the UKCCSG/SIOP 1992 04 clinical trial has shown that only 49% of cases had a GTR, with 5-year survival rates for STR of 22–47% and GTR of 67–80%. As part of the SIOP II Ependymoma trial the UK established a panel of experts in the treatment of Ependymoma from Neuro-oncology, Neuro-radiology and Neuro-surgery. Meeting weekly, cases are discussed to provide a consensus on radiological review, ensuring central pathological review, trial stratification and whether further surgery should be advocated on any particular case. Evaluation of the first 68 UK patients has shown a GTR in 47/68 (69%) of patients and STR in 21/68 (31%) of patients. Following discussion at EMAG it was felt that 9/21 (43%) STR patients could be offered early second look surgery. Following this 2nd look surgery the number of cases with a GTR increased to 56/68 (82%). There has been a clear increase in the number of patients for whom a GTR has been achieved following discussion at EMAG and prior to them moving forwards with their oncological treatment. This can only have beneficial effects in decreasing their risk of tumour recurrence or CSF dissemination and also in reducing the target volume for radiotherapy.

Ependymoma (EPN) is the second most common malignant paediatric brain tumour, which despite extensive genomic sequencing, no novel therapeutic options have been discovered. Multi-omics are anticipated to reveal dysregulated pathways that may be predictive of patient-specific biomarkers. Given the close association between gene expression, active biochemical signaling and metabolism, there is an unmet scientific challenge to determine whether EPN gene expression correlates with aberrant metabolic pathways, thus presenting therapeutic vulnerabilities. We first compared two distinct subgroups of EPN, PF-A and ST-RELA, identifying 115 metabolites and 1580 upregulated genes between the two subgroups, therefore validating previously reported genetic clustering of these two subtypes. We next integrated transcriptomics and metabolomics, comparing 28 intra-tumour tissue regions from eight primary PF-A EPN patients. Polar metabolites and RNA were simultaneously extracted from the same population of cells. RNAseq identified dysregulated genes and liquid chromatography-mass spectrometry (LC-MS) detected 98 significantly altered metabolites between 18 multi-regions, the majority mapping onto the arginine and proline pathways. Integration of genes and metabolites using pathway-based network analysis revealed 124 aberrant gene-metabolite interactions between intra-tumour regions, with large numbers occurring in the glucogenesis and glycine metabolic pathways in 6/8 patients. These may represent ubiquitous and therapeutically relevant metabolic pathways critical for EPN survival. Additionally, patients presented at least one unique intra-tumour genomic-metabolomic interaction, applicable for patient-tailored therapy. This is the first exploration of EPN multi-omic integration and intra-tumour heterogeneity. Selected drug targets predicated on aberrant gene-metabolite networks will be validated in multi-region patient-derived cell lines and orthotopic models using repurposed therapeutics.

Intracranial pressure (ICP) measurement is an important diagnostic tool in Neurosurgery. Until relatively recently, conventional monitoring has required that subjects be admitted to a hospital bed and the device is only able to be left in-situ for limited periods of time. We have evaluated a Telemetric ICP monitoring system that has been proven, by several other groups worldwide, to permit rapid, repeated and prolonged ICP measurement, in multiple environments. In our unit, 4 patients have been implanted to-date, between the ages of 4 and 16, manifesting a wide range of complex neurosurgical conditions. The sensors have been left in-situ for between 460 and 632 days. There have been no clinical complications and the system has been universally well tolerated. Clinical events, costs and patient experience were all assessed prior to and following implantation. Overall, there was a significant reduction in associated admissions (44.3%), imaging requirements (72.5%) and costs (50.0%). Subjective feedback from both the patients (where possible) and their families was overwhelmingly positive, partly due to (a) the system's ease of use, (b) its ability to reduce the number of admissions/tests required and (c) the facility for rapid measurement of ICP that permitted on-the-spot reassurance of concerns. Additionally, the ability to monitor ICP at home and/or whilst ambulant, has provided measurements that were hitherto inaccessible to our team, facilitating all the potential benefits that analysis of such information would provide. Indeed, we have seen the resultant management in each case has been completely altered by the availability of this data, reaffirming that the importance of being able to obtain it should not be underestimated. The combination of both this and the ability to markedly improve patient experience, along with generating significant cost-savings, lead the authors to suggest that the implantation of this system should be strongly considered in selected individuals.

OBJECT Endoscopic third ventriculostomy (ETV) has become a widely used method for CSF diversion when treating obstructive hydrocephalus. There are multiple recommendations on the transcortical ETV entry points, and some are specifically designed to provide a trajectory that avoids displacement to the eloquent periventricular structures. However, the morphology of the ventricular system is highly variable in hydrocephalus, and therefore a single best ETV trajectory may not be applicable to all cases. In the current study, 3 frequently quoted ETV entry points are compared in a cohort of pediatric cases with different degrees of ventriculomegaly. METHODS The images of 30 consecutive pediatric patients with varying degrees of ventriculomegaly were reviewed. Three-dimensional models were created using radiological analysis of anatomical detail and preoperative MRI scans in order to simulate 3 frequently quoted ETV trajectories for rigid neuroendoscopes. These trajectories were characterized based on the frequency and depth of tissue displacement to structures such as the fornix, caudate nucleus, genu of the internal capsule, and thalamus. The results are stratified based on ventricle size using the frontal horn ratio (FHR). RESULTS Eloquent areas were displaced in nearly all analyzed entry points (97%–100%). Stratifying the data based on ventricle size revealed that 1) lateral structures were more likely to be displaced in cases of intermediate ventriculomegaly (FHR < 0.4) using all 3 trajectories, whereas 2) the fornix was less likely to be displaced using more posteriorly placed trajectories for severe ventriculomegaly (FHR > 0.4). Allowing for minimal (2.4 mm) tissue displacement, a more posterior entry point was less traumatic for severe ventriculomegaly. CONCLUSIONS There is no single best ETV trajectory that fully avoids displacement of the eloquent periventricular structures. Larger ventricles require a more posteriorly placed entry point in order to reduce injury to the eloquent structures, and intermediate ventricles would dictate a medial entry point. These results suggest that the optimal entry point should be selected on a case-by-case basis after incorporating ventricle size.

INTRODUCTION: We report a four year old girl with autistic spectrum disorder who was being investigated for symptomatic central hypothyroidism and potential growth hormone deficiency. Brain MR imaging revealed a large solid / cystic suprasellar mass, splaying the optic chiasm and measuring 3 x 1.9 x 2.3 centimeters. The pituitary was obscured, other than a small portion of the infundibulum. The patient underwent a transphenoidal near total resection of the lesion, with necrotic cream-like material being encountered within the tumour bed. Post-operatively the patient developed transient diabetes insipidus but otherwise recovered well. The pathology of the lesion was consistent with a papillary craniopharyngioma with regions of stratified squamous epithelium accompanied by superficial goblet cells and ciliated cells. Subsequent next generation sequencing analysis of the lesion confirmed the presence of a BRAF V600E mutation (BRAFc.1799T>A p. (Val600Glu). To date, she has had no further therapy and remains stable nine months following surgery. LITERATURE REVIEW, METHODS AND RESULTS: Clinical cases of pediatric papillary craniopharyngioma were identified for those aged below 16 years via OVID and Pubmed search engines using clearly defined terms. Cases meeting the inclusion criteria are presented. CONCLUSION: We present one of the youngest patients published with a papillary craniopharyngioma, confirmed using histological and molecular analysis. This tumour type is extremely uncommon in the very young and encourages discussion about the most appropriate adjuvant therapy for tumour progression in such children, given the risks of radiotherapy to the developing brain and the increasing availability of oral BRAF inhibitor therapy.

Introduction Craniopharyngiomas are one of the most frequently diagnosed hypothalamo-pituitary tumors in childhood. The adamantinomatous histological subtype accounts for most pediatric cases, while the papillary variant is almost exclusively diagnosed in adults. Here, we report a case of papillary craniopharyngioma in a very young child, confirmed by molecular tissue analysis. Case report A 4-year-old girl was being investigated for symptomatic central hypothyroidism. Brain MR imaging revealed a large solid/cystic suprasellar mass, splaying the optic chiasm and measuring 3 × 1.9 × 2.3 cm. The patient underwent a transsphenoidal near total resection of the lesion, which was encased within a tumor capsule. Post-operatively, the patient developed transient diabetes insipidus but otherwise recovered well. The pathology of the lesion was consistent with a papillary craniopharyngioma with regions of stratified squamous epithelium accompanied by superficial goblet cells and ciliated cells. Subsequent next-generation sequencing analysis of the lesion confirmed the presence of a BRAF V600E mutation (BRAFc.1799T>A p. (Val600Glu). To date, she remains free from progression 1 year following surgery. Conclusion This is the youngest case published to date of papillary craniopharyngioma with a confirmed BRAF V600E mutation. The case encourages discussion about the most appropriate adjuvant therapy for tumor progression in such cases, given the risks of radiotherapy to the developing brain and the increasing availability of oral BRAF inhibitor therapy.

Selection of junior doctors into the British neurosurgical training program and subsequent speciality training have undergone several key changes over the past decade. Shift patterns in the era of the European Working Time Directive (EWTD) have had a major impact on surgical training. We discuss the national selection process, formalization of surgical simulation training and the need to encompass generic professional capabilities within the neurosurgical curriculum in order to create the "well-rounded surgeon". Future directions including hybrid cerebrovascular training, training in stereotactic radiosurgery, and dedicated training opportunities in spinal surgery.

Background Glioblastoma (GBM) is the most common primary brain malignancy in adults, yet survival outcomes remain poor. First line treatment is well established, however disease invariably recurs and improving prognosis is challenging. With the aim of personalizing therapy at recurrence, we have established a high content screening (HCS) platform to analyze the sensitivity profile of seven patient-derived cancer stem cell lines to 83 FDA-approved chemotherapy drugs, with and without irradiation. Methods Seven cancer stem cell lines were derived from patients with GBM and, along with the established cell line U87-MG, each patient-derived line was cultured in tandem in serum-free conditions as adherent monolayers and three-dimensional neurospheres. Chemotherapeutics were screened at multiple concentrations and cells double-stained to observe their effect on both cell death and proliferation. Sensitivity was classified using high-throughput algorithmic image analysis. Results Cell line specific drug responses were observed across the seven patient-derived cell lines. Few agents were seen to have radio-sensitizing effects, yet some drug classes showed a marked difference in efficacy between monolayers and neurospheres. In vivo validation of six drugs suggested that cell death readout in a three-dimensional culture scenario is a more physiologically relevant screening model and could be used effectively to assess the chemosensitivity of patient-derived GBM lines. Conclusion The study puts forward a number of non-standard chemotherapeutics that could be useful in the treatment of recurrent GBM, namely mitoxantrone, bortezomib and actinomycin D, whilst demonstrating the potential of HCS to be used for personalized treatment based on the chemosensitivity profile of patient tumor cells.

Glioblastoma is the most aggressive primary brain cancer with poor survival, but treatment strategies to improve prognosis have failed to materialise in over 30-years. Immune cells, in particular Tumour associated macrophages and microglia (TAMM) populate up to 40% of tumour bulk and are potential immunotherapy targets. However, functional roles of TAMM subpopulations still remain elusive and contradictory, due to limitations of existing mouse models and non-specific cell-surface markers used in human and rodent studies.

Histiocytic sarcoma (HS) of the central nervous system (CNS) is exceptionally rare in pediatric patients, historically associated with an exceptionally poor prognosis. Here, the authors present a novel case of protracted progression-free survival following surgical excision, radiotherapy and temozolomide. A 15-year-old Caucasian girl presented with a two-month history of headache, diplopia, vomiting, lethargy, weight loss and neurocognitive deterioration without gross neurological deficit on physical examination. Magnetic resonance imaging (MRI) of the brain identified a 5.8 × 4.7 × 4.0 cm lesion in the right frontal lobe with associated mass effect and no dissemination. Following two surgical procedures, gross total resection was achieved. Histology and immunohistochemistry confirmed HS, with strong CD163 staining. After focal radiotherapy with concomitant temozolomide, and a further seven cycles of temozolomide, the patient made an excellent recovery and is recurrence free without neurological deficit, 23 months following presentation. To the authors’ knowledge, this is the first incidence of a prolonged, functionally preserved and recurrence-free outcome following a diagnosis of HS within the CNS of a pediatric patient. We suggest early diagnosis prior to dissemination and complete surgical resection as an essential treatment goal in this rare disease.

BACKGROUND: Neurofibromatosis Type 2 (NF2) is a dominantly inherited tumour syndrome with a phenotype which includes bilateral vestibular (eighth cranial nerve) schwannomas. Conventional thinking suggests that these tumours originate at a single point along the superior division of the eighth nerve. METHODS: High resolution MRI was performed in children genetically proven to have NF2. The superior vestibular nerve (SVN) and inferior vestibular nerve (IVN) were visualised along their course with points of tumour origin calculated as a percentage relative to the length of the nerve. RESULTS: Out of 41 patients assessed, 7 patients had no identifiable eighth cranial nerve disease. In 16 patients there was complete filling of the internal auditory meatus by a tumour mass such that its specific neural origin could not be determined. In the remaining 18 cases, 86 discrete separate foci of tumour origin on the SVN or IVN could be identified including 23 tumours on the right SVN, 26 tumours on the right IVN, 18 tumours on the left SVN and 19 tumours on the left IVN. DISCUSSION: This study, examining the origins of vestibular schwannomas in NF2, refutes their origin as being from a single site on the transition zone of the superior division of the vestibular nerve. We hypothesise a relationship between the number of tumour foci, tumour biology and aggressiveness of disease. The development of targeted drug therapies in addition to bevacizumab are therefore essential to improve prognosis and quality of life in patients with NF2 given the shortcomings of surgery and radiation treatments when dealing with the multifocality of the disease.

The requirement for training surgical procedures without exposing the patient to additional risk is well accepted and is part of a national drive in the UK and internationally. Computer-based simulations are important in this context, including neurosurgical resident training. The objective of this study is to evaluate the effectiveness of a custom-built virtual environment in assisting training of a ventriculostomy procedure. The training tool (called VCath) has been developed as an app for a tablet platform to provide easy access and availability to trainees. The study was conducted at the first boot camp organized for all year-one trainees in neurosurgery in the UK. The attendees were randomly distributed between the VCath training group and the control group. Efficacy of performing ventriculostomy for both groups was assessed at the beginning and end of the study using a simulated insertion task. Statistically significant changes in performance of selecting the burr hole entry point, the trajectory length and duration metrics for the VCath group, together with a good indicator of improved normalized jerk (representing the speed and smoothness of arm motion), all suggest that there has been a higher-level cognitive benefit to using VCath. The app is successful as it is focused on the cognitive task of ventriculostomy, encouraging the trainee to rehearse the entry point and use anatomical landmarks to create a trajectory to the target. In straight-line trajectory procedures such as ventriculostomy, cognitive task-based education is a useful adjunct to traditional methods and may reduce the learning curve and ultimately improve patient safety.

OBJECT Surgeries for CNS tumors are frequently performed by general neurosurgeons and by those who specialize in surgical neurooncology. Subspecialization in neurosurgical practice has become common and may improve patient morbidity and mortality rates. However, the potential benefits for patients of having their surgeries performed by surgical neurooncologists remain unclear. Recently, a shift in patient care to those who practice predominantly surgical neurooncology has been promoted. Evidence for this practice is lacking and therefore requires fundamental investigation. METHODS The authors conducted a case-control study of neurooncology patients who underwent surgery for glioblastoma and anaplastic astrocytoma during 2006–2009. Outcomes were compared for patients whose surgery was performed by general neurosurgeons (generalists) or by specialist neurooncology neurosurgeons (specialists). An electronic record database and a picture archiving and communication system were used to collect data and assess the extent of tumor resection. Mortality rates and survival times were compared. Patient comorbidity and postoperative morbidity were assessed by using the Waterlow, patient handling, and falls risk assessment scores. Effects of case mix were adjusted for by using Cox regression and a hazards model. RESULTS Outcomes for 135 patients (65 treated by generalists and 70 by specialists) were analyzed. Survival times were longer for patients whose surgery was performed by specialists (p = 0.026) and after correction for case mix (p = 0.019). Extent of tumor resection was greater when performed by specialists (p = 0.005) and correlated with increased survival times (p = 0.004). There was a trend toward reduced surgical deaths when surgery was performed by specialists (2.8%) versus generalists (7%) (p = 0.102), and inpatient stays were significantly shorter when surgery was performed by specialists (p = 0.008). CONCLUSIONS The prognosis for glioblastoma multiforme remains dire, and improved treatments are urgently needed. This study provides evidence for a survival benefit when surgery is performed by specialist neurooncology neurosurgeons. The benefit might be attributable to increased tumor resection. Furthermore, specialist neurooncology surgical care may reduce the number of surgical patient deaths and length of inpatient stay. These findings support the recommendations for subspecialization within surgical neurooncology and advocate for care of these patients by specialists.

Central Nervous System (CNS) diseases and lesions are characterised by significant immune cell infiltration. In Glioblastoma Multiforme (GBM), a primary brain cancer, these Tumor Associated Macrophages and microglia (TAMM) may have pro-tumorigenic functions and play a key role in attenuating the host response to glioma. These cells can originate from the CNS itself as microglia or from the peripheral haematopoietic system as macrophages. Techniques currently used to separate the two populations in mice have used partially chimeric transplantation models or head shielded irradiation conditioning, however irradiation in particular leads to confounding pro-inflammatory effects in the peripheral environment. Furthermore, the reliability of using the cell surface markers CD45 high/low coupled with CD11b to distinguish central and peripheral populations has not been rigorously evaluated within the tumour microenvironment using non-irradiative methods. To circumvent these difficulties, we developed a Non-Myeloablative Conditioning (NMC) transplant regimen using low dose busulfan, achieving high CD45.1 donor marked peripheral blood haematopoietic chimerism (93%), without brain chimerism or blood brain barrier damage, thus maintaining CD45.2 marked homeostasis of the resident microglial population in the brain. Subsequent intracranial orthotopic implantation of a syngeneic mouse glioma line and whole brain flow cytometry, allowed us to characterise the proportion and type of peripheral immune cells infiltrating tumours. We observed that the proportion of central or peripheral TAMMs does not change significantly over time once the tumour is initially established. We also demonstrate that CD45/ CD11b, unreliably differentiates between central and peripheral TAMMs in the tumour environment, while the markers CD11b, Ly6C, MHCII, CD64 and MerTK, reliably differentiates subpopulations within peripheral derived TAMMs, (inflammatory monocytes, undifferentiated macrophages and macrophages) and central TAMMs, consisting of microglia, both in the NMC model and in un-transplanted mice with >95% purity. The combination of these techniques provides greater distinction of intra-tumoral myeloid cell subsets than previously described marker sets. The NMC transplantation model is simple and effective way of performing transplantation studies, and a powerful method of investigating immune cell interactions in CNS diseases, where a lack of perturbation of the system is important.

Objectives The management of paediatric craniopharyngiomas was traditionally complete resection (CR), with better reported tumour control compared to that by partial resection (PR) or limited surgery (LS). The subsequent shift towards hypothalamic sparing, conservative surgery with adjuvant radiotherapy (RT) to any residual tumour aimed at reducing neuroendocrine morbidity, has not been systematically studied. Hence, we reviewed the sequelae of differing management strategies in paediatric craniopharyngioma across three UK tertiary centres over four decades. Methods Meta-data was retrospectively reviewed over two periods before (1973–2000 (Group A: n = 100)) and after (1998–2011 (Group B: n = 85)) the introduction of the conservative strategy at each centre. Results Patients had CR (A: 34% and B: 19%), PR (A: 48% and B: 46%) or LS (A: 16% and B: 34%), with trends reflecting the change in surgical approach over time. Overall recurrence rates between the two periods did not change (A: 38% vs B: 32%). More patients received RT in B than A, but recurrence rates were similar: for A, 28% patients received RT with 9 recurrences (32%); for B, 62% received RT with 14 recurrences (26%). However, rates of diabetes insipidus (P = 0.04), gonadotrophin deficiency (P P = 0.001) were lower in B than those in A. In contrast, post-operative obesity (BMI SDS >+2.0) (P = 0.4) and hypothalamic (P = 0.1) and visual (P = 0.3) morbidity rates were unchanged. Conclusion The shift towards more conservative surgery has reduced the prevalence of hormone deficiencies, including diabetes insipidus, which can be life threatening. However, it has not been associated with reduced hypothalamic and visual morbidities, which remain a significant challenge. More effective targeted therapies are necessary to improve outcomes.

INTRODUCTION: The radiological diagnosis of childhood diffuse intrinsic pontine glioma (DIPG) has historically been founded upon characteristic magnetic resonance imaging metrics. Modern neuro-imaging now incorporates multi-parametric physiological assessments including perfusion and diffusion sequences. Concurrently, histological analysis of presumed DIPGs in the molecular era has resulted in a proportion being re-classified as pontine embryonal tumors; lesions with contrasting management and potential outcomes. We postulated whether integrating modern multi-parametric imaging could discriminate between the two tumors at presentation. METHODS: A retrospective diagnostic MRI analysis of children that had undergone biopsy for presumed DIPG at Manchester and Liverpool Pediatric Neuro-oncology Centers over the last decade was performed. Perfusion was assessed by both arterial spin labeling and dynamic contrast susceptibility weighted techniques. RESULTS: Thirteen patients were identified (median age 4.2 (2.6 – 7.8) years). All lesions had characteristic, non-differentiating T1, T2 and FLAIR appearances, with varying contrast enhancement. Ten were confirmed DIPG (Grade II (3), Grade III (2), Grade IV (4), NOS (1)), while three were embryonal tumors. Reduced perfusion was identified in all embryonal lesions and Grade II DIPGs, whereas increased perfusion was observed in Grade III and IV DIPGs. Diffusion restriction was observed in embryonal lesions compared to Grade II DIPGs. CONCLUSIONS: Low perfusion within a presumed DIPG may reflect a lower grade of glioma or indeed an embryonal pontine tumor, particularly if accompanied by overt intra-lesional diffusion. While requiring validation in larger cohorts, we propose perfusion imaging is a vital adjunct in DIPG radiological phenotyping and should be employed at presentation.

Glioblastoma Multiforme (GBM) is the most common primary brain tumour in adults, yet survival outcomes remain poor. First line treatment is well established but with disease recurrence almost inevitable, improving prognosis is challenging. With the aim of personalising therapy at recurrence we have established a high content screening (HCS) platform to analyse the sensitivity profile of seven patient-derived cancer stem cell lines to 82 FDA-approved chemotherapy drugs, with and without irradiation. Seven cancer stem cell lines were derived from patients with GBM, or GBM variants. Along with the established cell line U87-MG, each patient-derived line was cultured in tandem in serum-free conditions as adherent monolayers and three-dimensional neurospheres. Chemotherapeutics were screened at multiple concentrations and cells double-stained to observe their effect on both cell death and proliferation. Sensitivity was classified using high-throughput algorithmic image analysis. Cell line specific drug responses were observed across the seven patient-derived cell lines. Few agents were seen to have radio-sensitising effects, yet some drug classes showed a marked difference in efficacy between monolayers and neurospheres. In vivo validation of six drugs indicated that cell death readout in a three-dimensional culture scenario is a more physiologically relevant screening model, and can be used effectively to assess the chemosensitivity of patient-derived GBM lines. The study puts forward a number of non-standard chemotherapeutics that could be useful in the treatment of recurrent GBM, whilst demonstrating the potential of HCS to be used for personalised treatment based on the chemosensitivity profile of patient tumour cells.

MPS IIIC is caused by mutations in the HGSNAT gene. HGSNAT deficiency affects lysosomal catabolism of heparan sulfate (HS), resulting in widespread CNS pathology in infants and children, leading to behavioural problems, cognitive decline and, finally, dementia and death before adulthood. Currently there are no existing treatments for MPS IIIC and the development of treatments is difficult as the deficient enzyme cannot cross the blood brain barrier or diffuse between cells. We have developed an adeno-associated virus (AAV) based gene therapy for MPS IIIC which is efficacious in a MPS IIIC murine model via injection into the brain parenchyma. Although effective in a small murine brain, the architecture and volume is considerably different from a human brain, and the failure of previous clinical trials for AAV vectors using intraparenchymal injection, means that large animal experiments are essential in optimising widespread distribution needed for clinical efficacy. Due to the inability of HGSNAT to cross-correct cells, intracerebral delivery of vector needs to target the maximum number of cells, and with the use of convection enhanced delivery (CED) this can be achieved. CED has the potential to treat diseases with global pathology such as MPS IIIC as it overcomes the issues with current delivery methods and can be administered to multiple sites. We compared different conditions to determine optimal vector spread of an AAV9-GFP vector in the sheep brain, which is 130mL in volume, at clinically applicable volumes and titres whilst keeping volume identical throughout. We compared 4 intraparenchymal sites, against intraventricular injection, and compared different flow rates at 2 single intraparenchymal sites. We found a rate of 1μL/min into the corpus striatum produced the greatest vector distribution, whilst intraventricular outcomes were comparatively poor. However, further studies are currently ongoing to improve this further with the aim of determining the optimal delivery system for gene therapy of MPS IIIC.

This study was designed to evaluate an online prognosis prediction calculator intended for use in patients with glioblastoma by comparison with actual outcomes in 2 UK-based neurosurgical units. Glioblastoma multiforme (GBM) is the most common and most aggressive primary brain tumor in adults. With an incidence rate of 2–3 cases per 100 000 per year, GBM accounts for 22.6% of all brain and central nervous system tumors.1 The overall median survival is reported as 7.6–9.4 months,2,3 but this can reach 14 months with a 2-year survival rate of 27% in clinical trial groups.4 It is therefore a conspicuous clinical entity and conveys a poor prognosis. In 2005, a phase III randomized trial organized by the European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) Clinical Trials Group demonstrated a survival benefit conveyed by radiotherapy plus concomitant and adjuvant temozolomide in the treatment of patients with newly diagnosed glioblastoma.4 In an exploratory subanalysis of the EORTC/NCIC trial data, Gorlia et al. subsequently identified a variety of factors that were predictive of overall survival, including therapy administered, age, extent of surgery, mini-mental score examination, administration of corticosteroids, World Health Organization (WHO) performance status, and O-methylguanine-DNA methyltransferase (MGMT) promoter methylation status.5 This is in agreement with the most consistently reported prognostic factors for GBM (age, extent of surgical resection, and performance status),6–8 but promoter region methylation of the MGMT enzyme, which repairs DNA damaged by alkylating agents, and MMSE have also previously been associated with improved prognosis.9,10 On the basis of their findings, Gorlia et al. developed 3 nomograms, each intended to predict the survival times among patients with newly diagnosed GBM on the basis of individual-specific combinations of prognostic factors.5 These nomograms have been made available online as a “GBM Calculator” and are intended for use in patient counseling and treatment selection and in the design and interpretation of clinical trials.11 The nomograms were developed by correlating all of the identified predictive factors with outcome and combining them to give a predicted median survival and a 2-year survival probability. This was done in 3 distinct populations to separate the potential skewing effect of MGMT promoter methylation status and treatment given. Population 1 was the entire group (n = 573). Population 1 was stratified using the factors shown in Table 1. Table 1: Stratification criteria for GBM calculator model 1 In the authors' experience, many patients would like to know their prognosis at diagnosis to understand their condition and to plan practical and financial affairs, and it certainly helps them and their families to start the anticipatory grieving process necessary in terminally ill patients.12 The GBM calculator promised to be a very helpful clinical tool in this respect. Before offering this information to patients, the authors wanted to validate its use in a local patient population, because it was felt that giving potentially incorrect information would be unhelpful and insensitive and would undermine confidence in the treating team.

Distant intraventricular metastasis is extremely rare in childhood craniopharyngioma. Here, we report the isolated posterior ventricular recurrence of an adamantinomatous craniopharyngioma, in a child previously treated with surgery and proton beam therapy for local progression. The importance of surveillance imaging is highlighted, while specific surgical approaches and techniques are considered.

Object Choroid plexus carcinomas (CPCs) are rare pediatric tumors with a generally poor prognosis. Although the role of surgery is well recognized, the role of adjuvant chemotherapy and radiation therapy remains unclear. In this paper, the authors' goal was to assess the role of second-look surgery and neoadjuvant ifosfamide, carboplatin, etoposide (ICE) chemotherapy in the management of CPC and to study neurocognitive outcome. Methods The authors performed an institutional retrospective review of patients in whom CPC was diagnosed between 1985 and 2006 at the Hospital for Sick Children in Toronto. Fourteen patients (7 boys and 7 girls) were included. The median age at diagnosis was 18.6 months (range 1.1–65.3 months). Four patients had evidence of metastatic disease at diagnosis. Two of the 14 patients underwent gross-total resection during initial surgery; 12 of the patients received neoadjuvant chemotherapy, 10 of whom underwent second surgery. In total, of 12 patients who received chemotherapy with a curative intent, 11 underwent a greater than 95% resection. Neoadjuvant ICE chemotherapy was given prior to second surgery (median 4 cycles, range 2–5 cycles) and was continued after second resection for a median total of 7 cycles (range 4–16 cycles). Results No tumor progression was observed during chemotherapy prior to second surgery. Five patients subsequently experienced tumor progression/relapse. At a median follow-up of 6.9 years (range 1.9–18.5 years), 8 patients are alive. None of the survivors received radiation therapy. However, 6 of 8 display significant neurocognitive and/or sensorial deficit. Conclusions In this experience, second surgery following neoadjuvant ICE chemotherapy led to a high rate of complete or near-complete resection. Chemotherapy appears to facilitate second-look surgery, in particular through a reduction of intraoperative blood loss. Despite radiation avoidance, the majority of survivors experienced significant neurocognitive impairment.

OBJECT Choroid plexus carcinomas (CPCs) are rare brain tumors originating from the ventricular choroid plexus. They account for 2%–4% of all pediatric brain tumors and are most frequently seen in very young children. This pediatric proclivity, in combination with a marked vascularity, renders an aggressive resection a difficult and often dangerous endeavor. Blood losses of several total blood volumes in small children are not uncommon, sometimes forcing the neurosurgeon to abort the procedure, often leaving residual tumor. Great extent of tumor resection is an accepted beneficial factor for overall survival. Therefore, a second resection usually follows the administration of adjuvant chemotherapy. Second-look surgery appears to be associated with markedly decreased blood loss. Histological examination of specimens obtained at a second intervention shows decreased vascularity and fibrotic changes in tumor tissue. At the Hospital for Sick Children in Toronto, this empirical finding led to the strategy of neoadjuvant chemotherapy to minimize blood loss and maximize cytoreduction. The authors undertook this study to assess the potentially beneficial effect of neoadjuvant chemotherapy on blood loss during surgery for CPCs. METHODS In this retrospective cohort review, the demographic, clinical, and treatment parameters of 22 consecutive patients diagnosed with CPC are presented. All underwent surgical treatment at the Hospital for Sick Children from 1982 to 2013. Special attention was given to the impact of neoadjuvant chemotherapy on extent of resection and intraoperative blood loss. Extent of resection was calculated based on perioperative neuroimaging, and amount of blood loss was estimated based on transfusion parameters and perioperative changes in hematocrit. RESULTS Ten patients did not receive neoadjuvant chemotherapy, and 12 were treated with 2–5 cycles of ICE (ifosfamide, carboplatin, etoposide) chemotherapy in a neoadjuvant fashion. The 22 patients included in the study underwent a total of 37 tumor resection surgeries. In all of the cases in which neoadjuvant chemotherapy was used, at least a near-total resection (> 95% of tumor volume) was achieved. Patients who underwent gross-total resection had prolonged overall survival. Of the 37 resections, 18 were performed after chemotherapy. Mean blood loss in the neoadjuvant chemotherapy group was 22% of total estimated blood volume as opposed to 96% in patients without preoperative chemotherapy. CONCLUSIONS In children with CPC, the administration of neoadjuvant chemotherapy decreases intraoperative blood loss and increases extent of resection with a significant positive effect on overall survival.

OBJECT Over the last 20 years, several intraoperative adjuncts, including ultrasonography, neuronavigation, and angiography, have been said to aid the intraoperative localization and resection of cerebral arteriovenous malformations (AVMs). The authors assessed the value of intraoperative Doppler ultrasonography in conjunction with neuronavigation during surgery for cerebral AVMs in the pediatric population. METHODS The authors reviewed all cranial AVM resections performed by a single surgeon at their institution in the period from 2007 to 2013 and here describe their experience and results in a series of 20 consecutive AVM resections in 19 pediatric patients. Intraoperative Doppler ultrasonography had been used in conjunction with preoperative CT or neuronavigational MRI. Preoperative and postoperative clinical findings, patient age, and Spetzler-Martin AVM grade were identified in all patients. RESULTS All patients, whose ages ranged from 2 to 16 years, underwent craniotomy and excision of an AVM, which was supratentorial in 18 cases and infratentorial in 2. Patients in 11 cases underwent preoperative embolization, and all other patients underwent cerebral angiography prior to surgery, except for 2 patients who were urgently surgically treated because of low Glasgow Coma Scale scores and associated hematoma. Spetzler-Martin Grades I (3 cases), II (6), III (7), and IV (4) AVMs were represented in this series. Intraoperative Doppler ultrasound provided high-quality images in all cases and demonstrated the location, size, and flow characteristics of the AVM and any associated hematoma. Delayed postoperative cerebral angiography demonstrated successful AVM resection in all cases. An assessment of clinical outcomes revealed no new long-term neurological deficits at 3 months postoperatively. CONCLUSIONS Intraoperative Doppler ultrasonography is a reliable and useful tool for intraoperative localization and guidance for AVM resection in the pediatric population. When used in conjunction with neuronavigation equipment and modern microscopes, this technique has shown a very high complete resection rate with extremely low associated morbidity.

Importance Meningiomas and schwannomas are usually sporadic, isolated tumors occurring in adults older than 60 years and are rare in children and young adults. Multiple schwannomas and/or meningiomas are more frequently associated with a tumor suppressor syndrome and, accordingly, trigger genetic testing, whereas solitary tumors do not. Nevertheless, apparently sporadic tumors in young patients may herald a genetic syndrome. Objective To determine the frequency of the known heritable meningioma- or schwannoma-predisposing mutations in children and young adults presenting with a solitary meningioma or schwannoma. Design, Setting, and Participants Using the database of the Manchester Centre for Genomic Medicine, this cohort study analyzed lymphocyte DNA from young individuals prospectively referred to the clinic for genetic testing between January 1, 1990, and December 31, 2016, on presentation with a single meningioma (n = 42) or schwannoma (n = 135) before age 25 years. Sequencing data were also examined from an additional 39 patients with neurofibromatosis type 2 who were retrospectively identified as having a solitary tumor before age 25 years. Patients with schwannoma were screened for NF2 , SMARCB1, and LZTR1 gene mutations, while patients with meningioma were screened for NF2 , SMARCB1 , SMARCE1, and SUFU . Main Outcomes and Measures The type of underlying genetic mutation, or lack of a predisposing mutation, was associated with the presenting tumor type and subsequent development of additional tumors or other features of known schwannoma- and meningioma-predisposing syndromes. Results In 2 cohorts of patients who presented with an isolated meningioma (n = 42; median [range] age, 11 [1-24] years; 22 female) or schwannoma (n = 135; median [range] age, 18 [0.2-24] years; 60 female) before age 25 years, 16 of 42 patients (38%) had a predisposing mutation to meningioma and 27 of 135 patients (20%) to schwannoma, respectively. In the solitary meningioma cohort, 34 of 63 patients (54%) had a constitutional mutation in a known meningioma predisposition gene. Twenty-five of 63 patients (40%) had a constitutional NF2 mutation, and 9 (14%) had a constitutional SMARCE1 mutation. In the cohort of those who developed a solitary schwannoma before age 25 years, 44 of 153 patients (29%) had an identifiable genetic predisposition. Twenty-four patients (55%) with a spinal schwannoma had a constitutional mutation, while only 20 (18%) with a cranial schwannoma had a constitutional predisposition ( P LZTR1 mutation (3 were vestibular schwannomas and 1 was a nonvestibular schwannoma), and 9 (8.5%) had an NF2 mutation. Conclusions and Relevance A significant proportion of young people with an apparently sporadic solitary meningioma or schwannoma had a causative predisposition mutation. This finding has important clinical implications because of the risk of additional tumors and the possibility of familial disease. Young patients presenting with a solitary meningioma or schwannoma should be referred for genetic testing.

Background Positional plagiocephaly is the most common cause of cranial asymmetry. The underlying cause of Chiari-1 malformation has many possible theories, and anecdotally some pediatric neurosurgeons have had experience of severe cases of positional brachycephaly with Chiari-1. However, to date, there have been no published cases linking nonsynostotic plagiocephaly with Chiari-1 malformation. Case Description An 18-month-old boy presented with a head injury. On examination he had a Glasgow Coma Score of 15 with no focal neurologic deficits, but he was noted to have marked posterior brachycephaly. A computed tomography scan showed a slim left-sided hemispheric acute subdural hematoma with no mass effect, which was treated conservatively. Of note, all of his cranial vault sutures were open, and a diagnosis of incidental positional plagiocephaly was made. Subsequent magnetic resonance imaging as part of a work-up to exclude nonaccidental injury showed a small posterior fossa with a steep tentorium and herniation of the cerebellar tonsils to the level of the body of the second cervical vertebra. Conclusions Chronic hindbrain herniation is well reported in cases of craniosynostosis, but to our knowledge this is the first published case associated with nonsynostotic deformational plagiocephaly. We hypothesize that severe posterior plagiocephaly can cause disproportion of the posterior fossa: hindbrain volume ratio and acquired chronic cerebellar herniation. Nevertheless, positional plagiocephaly and Chiari-1 are common entities, and it is possible that the dual diagnoses were coincidental in this case. This report serves to raise awareness of a putative causal relationship between positional plagiocephaly, reduced posterior fossa volume, and hindbrain herniation.

Dynamic susceptibility contrast-enhanced magnetic resonance (MR) imaging in tumors is restricted by relaxivity effects, which may obscure any abnormality of first-pass kinetics in the re-circulation phase. The purposes of this study were a) to document the magnitude of relaxivity effects with a variety of commonly used MR susceptibility imaging techniques; and b) to determine whether the re-circulation phase of the first-pass curve in tumors differs from that in normal tissue. We have confirmed that residual relaxivity effects can be eliminated from dynamic susceptibility contrast-enhanced data by several techniques. Application of these methods to enhancing vascular tumors allows detection of abnormalities in the re-circulation phase, which would otherwise be obscured. These abnormalities are independent of relative cerebral blood volume (rCBV) and presumably represent deviations from the predicted gamma variat flow pattern seen in normal tissues. We believe that the parameter rR described here provides an indicator of the chaotic nature of neovascular angiogenesis, which may be of benefit in diagnosis and management.

This study describes a method for imaging brain tumors that combines T1-weighted (T1W) and T2*-weighted (T2*W) dynamic contrast-enhanced acquisitions. Several technical improvements have been made to produce high-quality three-dimensional mapping of endothelial permeability surface area product (k) and leakage space (vl), based on T1W data. Tumor blood volume maps are obtained from T2*W images with a complete removal of residual relaxivity effects. The method was employed in 15 patients with brain tumors (5 gliomas, 5 meningioma, and 5 acoustic schwannoma). Mean values of vl were significantly greater in acoustic schwannomas (53% +/- 9%) than in meningiomas (34% +/- 7%) or gliomas (22% +/- 4%). Mean values of vl in meningioma were significantly greater than those of gliomas. Mean values of rCBV correlated closely with k. There was also a positive correlation between k and vl for pixels with low k values. This relationship was weaker in areas of high k. The highest mean ratios of k to vl (k(ep)) were seen in two patients with glioblastoma, one patient with transitional cell meningioma, and one patient with angioblastic meningioma. Pixel-by-pixel comparison showed a strong correlation between rCBV and k in 11 of 15 patients. However, decoupling between pixel-wise rCBV and k was found in four patients who had lesions with moderate k and vl elevation but no increase of rCBV. Results from this study suggest that in assessing the angiogenic activities in brain tumors it is advisable to monitor simultaneously changes in tumor blood volume, vessel permeability, and leakage space of tumor neovasculature.

Young children with significant ventricular dilatation or large intracranial fluid spaces often have a very thin cortical mantle as a result of persistently raised intracranial pressure. This rim of cortex has a tendency to fall away from the dura into the cavity during and after intracranial surgery, due to the lack of support, once the pressure in the fluid cavity has been reduced. This can lead to tearing of cortical bridging veins and the formation of post-operative subdural haematomas.We describe a simple technique that attempts to prevent this phenomenon occurring using tissue glue. Once the craniotomy has been performed and the dura has been formally opened, tissue glue is applied to the underside of the dura around the edge of the wound, prior to corticotomy.This results in the cortical mantle adhering to the undersurface of the dura and prevents the mantle from falling into the cavity either during the procedure or post-operatively.

Choroid plexus tumors consist of papillomas and carcinomas. A variety of germline and somatic genetic changes have been demonstrated for each of these subtypes. In this paper, the authors summarize the current knowledge of the genetic bases of these tumors.

In the UK approximately 4000 patients are diagnosed with brain tumours each year. Many patients undergo CT scans of the chest, abdomen and pelvis as part of the investigation of such tumours. We aimed to determine the value of CT body scans in patients with newly diagnosed brain tumours.We retrospectively reviewed the minutes of our neuro-oncology multidisciplinary team (MDT) meetings over a 12-month period to identify patients with a new radiological diagnosis of a brain tumour. Patients were divided into groups based on radiological diagnosis. Histology results were obtained for patients who underwent surgery. Results of CT body scans were obtained.A total of 261 patients were identified. Sixty percent had radiological primary brain tumours and 40% had secondary brain tumours. Concordance between radiological and histological diagnoses was high (97% for radiological primary brain tumours, and 83% for radiological secondary brain tumours). CT body scans demonstrated primary lesions in 90% of radiological secondary brain tumours. Thirty-four percent of patients with a radiological diagnosis of primary brain tumour underwent CT body scans. The majority of these scans were normal (78%).The ability of a specialist neuro-oncology MDT to correctly identify primary and secondary brain tumours on initial imaging is high. If the radiological diagnosis is of a secondary brain tumour, then CT body scans are essential. If the radiological diagnosis is of a primary brain tumour, then CT scans of the body are likely to add little to patient management.

Ventriculoperitoneal shunt (VPS)-dependent children require abdominal surgery for many reasons. Our objective was to quantify the risk of abdominal surgery on VPS survival and to determine whether timing of abdominal intervention impacts on shunt outcome.Retrospective data collection was performed on all children undergoing primary VPS insertion or revision over 2 years (1/1/08-31/12/10). All shunt interventions were categorised into two groups: those undergoing additional "Abdominal surgery" (AS) versus those undergoing "Shunt-only" (SO). Kaplan-Meier survival curves were devised and analysed using log-rank. In the AS group, we compared shunt survival for shunts inserted at various "Time from abdominal surgery" (TAS). We conducted a control analysis to compare shunt survival in AS, SO and a control "clean general surgery" (SG) group. Chi-squared test was used to determine the cause of shunt failure in these three groups.Three hundred and forty two shunts from 109 patients were included. Twenty patients contributed 118 shunts to the AS group. Median shunt survival was 3.68 months (95% CI = 1.01-6.47) and 22.6 months (95% CI = 8.76-36.4) in the AS and SO groups, respectively (log-rank = 16.6, p0.001). For each additional abdominal intervention, the risk of shunt failure increased by 55.4% (p0.001). Median shunt survival was 1.48 months (95% CI = 0.00-3.09, p0.001), if shunt insertion occurred within 1 year of abdominal surgery. Beyond 1 year, median shunt survival increased five-fold to 7.65 months (95% CI = 0.00-20.1, log-rank = 23.2, p0.001). There was a 29% reduction in risk of shunt failure per year interval between a shunt and an abdominal surgery (95% CI = 0.11-0.44, p0.005). Our control analysis confirmed that shunts in the AS group had worst survival and infection (p0.001).Additional abdominal surgery shortens VPS lifetime and increases risk of infection. Delaying abdominal surgery from a shunt intervention or vice versa by at least 1 year may prolong shunt survival.