Chiari I malformation (CIM) rarely occurs alongside hydrocephalus (7–10

Background Survivors of childhood medulloblastoma are particularly susceptible to late effects because of the location of the tumour and the treatment required to achieve a cure. Living with these long-term toxicities is challenging and greater understanding of the impact of the disease and treatment have on health-related quality of life (HRQoL) is needed. Procedure We report a cross-sectional study to assess patient HRQoL outcomes for 52 long-term survivors of medulloblastoma aged 1–25 years of age at diagnosis and treated during a ten-year period at The Royal Marsden Hospital. Child self-reports and parent – proxy reports of PedsQL scores correlate with clinical information, long-term toxicity (assessed using CTCAE) and neurocognitive assessment (using WISC-IV) to examine the impact that disease and treatment have on HRQoL after treatment. Results Reported late toxicities included ataxia (62%), hearing impairment (59%), endocrine disorders (57%) and memory impairment (44%). Reduced HRQoL outcome scores for patients showed a significant correlation with reduced verbal comprehension (0.51; p=0.025), and processing speed (0.5; p=0.04). Memory impairment showed significant association with the cancer module PedsQL (p=0.024) scores. Parents’ perception of their child’s quality of life was lower than the patient’s self-assessment (mean 55.9 for parents and 63.8 for patients, p=0.004). Conclusions The findings from this study confirm the impact of late toxicities and neurocognitive sequelae on HRQoL in patients previously treated for medulloblastoma in childhood and adolescence. In particular verbal comprehension, processing speed and memory impairment influence patient reported outcomes in this cohort.

© BMJ Publishing Group Limited 2022. No commercial reuse. See rights and permissions. Published by BMJ. DESCRIPTION Postoperative pseudomeningoceles are characterised by extradural accumulation of cerebrospinal fluid (CSF) leaked from a surgical wound into the subcutaneous space. Giant cranial pseudomeningoceles are extremely rare. Herein, we describe a case of focal seizures and haemiparesis caused by decompression of a giant cranial pseudomeningocele. An otherwise healthy man in his 40s presented with generalised tonicclonic seizures. Imaging demonstrated a 4.7×4.0×3.6 cm extraaxial right parasagittal lesion suggestive of a meningioma (figure 1A). His seizures were controlled with antiepileptic drugs and he underwent a right parietal craniotomy for resection of meningioma. The procedure was uneventful. Postoperatively, he developed a persistent large pseudomeningocele, with no features of hydrocephalus. We managed the pseudomeningocele conservatively, expecting it would settle with time. Histopathology confirmed a WHO grade 1 meningioma. He represented 3 months following his operation reporting problem of headache and a recent progressive increase in the size of the pseudomeningocele. On examination of the wound site, there was a very large fluctuant collection (>20 cm). He was neurologically intact. CT imaging of the brain confirmed the presence of a large subcutaneous CSF collection in communication with the surgical site. The pseudomeningocele had a large extracranial component and a relatively smaller intracranial component underlying the craniotomy site, causing mass effect on the underlying brain (figure 1B). We performed a highvolume lumbar puncture and applied a pressure bandage over the site of the pseudomeningocele. He had an opening pressure of 14 cmH2O, 45 mL of CSF was drained and closing pressure was 8 cmH20. Following the lumbar puncture, over the next 48 hours, he developed focal seizures affecting his left arm and leg and progressive left upper and lower limb weakness. On examination, he had power 0/5 in his left lower limb and 3/5 in his left upper limb. CT imaging demonstrated near complete resolution of the intracranial component of the pseudomeningocele; however, there was a new focal hypodensity in the underlying brain, suggestive of oedema (figure 2A). He was given highdose steroids. MR imaging, obtained the following day, confirmed T2 high signal in the right post central gyrus, extending into the paracentral lobule and corona radiata representing oedema (figure 2B). There were no areas of restricted diffusion to

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Arachnoid cysts are CSF-containing entities that rarely are symptomatic or warrant neurosurgical intervention. In addition, infection of these lesions is an even rarer event, with only four reports in the literature capturing this. In this report, we present the case of a 79-year-old man presenting with paraparesis, secondary to a right parasagittal meningioma, with an incidental asymptomatic right sylvian arachnoid cyst (Galassi type II). The initially planned surgery was postponed for 3 months, due to COVID-19 restrictions, and he was kept on high dose of steroids. Following tumour resection, the patient developed bilateral subdural empyemas with involvement of the arachnoid cyst, requiring bilateral craniotomies for evacuation of the empyemas and drainage of the arachnoid cyst. Suppuration of central nervous system arachnoid cysts is a very rare complication following cranial surgery with the main working hypotheses including direct inoculation from surrounding inflamed meninges or haematogenous spread secondary to systemic bacteraemia, potentiated by steroid-induced immunosuppression. Even though being a rarity, infection of arachnoid cysts should be considered in immunosuppressed patients in the presence of risk factors such as previous craniotomy.

INTRODUCTION AND OBJECTIVES:The novel severe acute respiratory syndrome coronavirus 2 (COVID-19) pandemic has had drastic effects on global healthcare with the UK amongst the countries most severely impacted. The aim of this study was to examine how COVID-19 challenged the neurosurgical delivery of care in a busy tertiary unit serving a socio-economically diverse population. METHODS:A prospective single-centre cohort study including all patients referred to the acute neurosurgical service or the subspecialty multidisciplinary teams (MDT) as well as all emergency and elective admissions during COVID-19 (18th March 2020-15th May 2020) compared to pre-COVID-19 (18th of January 2020-17th March 2020). Data on demographics, diagnosis, operation, and treatment recommendation/outcome were collected and analysed. RESULTS:Overall, there was a reduction in neurosurgical emergency referrals by 33.6% and operations by 55.6% during the course of COVID-19. There was a significant increase in the proportion of emergency operations performed during COVID-19 (75.2% of total, n=155) when compared to pre-COVID-19 (n = 198, 43.7% of total, p < 0.00001). In contrast to other published series, the 30-day perioperative mortality remained low (2.0%) with the majority of post-operative COVID-19-infected patients (n = 13) having underlying medical co-morbidities and/or suffering from post-operative complications. CONCLUSION:The capacity to safely treat patients requiring urgent or emergency neurosurgical care was maintained at all times. Strategies adopted to enable this included proactively approaching the referrers to maintain lines of communications, incorporating modern technology to run clinics and MDTs, restructuring patient pathways/facilities, and initiating the delivery of NHS care within private sector hospitals. Through this multi-modal approach we were able to minimize service disruptions, the complications, and mortality.

Abstract Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an “intrinsic” spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. Significance: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion–positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype. See related video: https://vimeo.com/438254885 See related commentary by Szulzewsky and Cimino, p. 904. This article is highlighted in the In This Issue feature, p. 890

Abstract Gliomas often present clinically with seizures. Tumour-associated seizures can be difficult to control with medication. A deeper understanding of the cellular mechanisms underlying tumour-associated seizures would provide a basis for developing new treatments. Here, we investigate epileptic discharges in peritumoral cortex using living human brain tissue donated by people having a craniotomy for glioma resection (REC approval, 18/SW/002). The brain tissue was cut into thin slices, which preserved the architecture of the glioma and the adjacent healthy brain. The brain slices were incubated in 5-aminolevulinic acid to make the glioma cells fluorescent. This enabled us to make electrophysiological recordings of brain activity across the boundary between glioma and brain. We recorded from brain slices of 5 participants with glioblastoma and 4 participants with oligodendroglioma (WHO grade II – III). Spontaneous “seizure-like” discharges were recorded in brain slices from 5/8 participants (3 GBM, 2 oligodendroglioma) who reported seizures and from one participant (GBM) who had not had any clinical seizures. Further analysis of the seizure-like discharges revealed that they could be subdivided into two distinct types based on the major frequencies in the discharge. We concluded that human brain slices from people with either a low-grade or a high-grade glioma can generate spontaneous seizure-like discharges. The living human brain tissue preparation gives us a platform to study the mechanisms of tumour-associated seizures and how abnormal neural activity affects glioma growth.

ObjectivesTo determine current epidemiology and clinical characteristics of cerebrospinal fluid (CSF) shunt surgery, including revisions.MethodsA retrospective, multicentre, registry-based study was conducted based on 10 years’ data from the UK Shunt Registry, including primary and revision shunting procedures reported between 2004 and 2013. Incidence rates of primary shunts, descriptive statistics and shunt revision rates were calculated stratified by age group, geographical region and year of operation.Results41 036 procedures in 26 545 patients were submitted during the study period, including 3002 infants, 4389 children and 18 668 adults. Procedures included 20 947 (51.0%) primary shunt insertions in 20 947 patients, and 20 089 (49.0%) revision procedures. Incidence rates of primary shunt insertions for infants, children and adults were 39.5, 2.4 and 3.5 shunts per 100 000 person-years, respectively. These varied by geographical subregion and year of operation. The most common underlying diagnoses were perinatal intraventricular haemorrhage (35.3%) and malformations (33.9%) in infants, tumours (40.5%) and malformations (16.3%) in children, and tumours (24.6%), post-haemorrhagic hydrocephalus (16.2%) and idiopathic normal pressure hydrocephalus (14.2%) in adults. Ninety-day revision rates were 21.9%, 18.6% and 12.8% among infants, children and adults, respectively, while first-year revision rates were 31.0%, 25.2% and 17.4%. The main reasons for revision were underdrainage and infection, but overdrainage and mechanical failure continue to pose problems.ConclusionsOur report informs patients, carers, clinicians, providers and commissioners of healthcare, researchers and industry of the current epidemiology of shunting for CSF disorders, including the potential risks of complications and frequency of revision.

ABSTRACTPaediatric high grade glioma and diffuse midline glioma (including DIPG) are comprised of multiple biological and clinical subgroups, the majority of which urgently require novel therapies. Patient-derivedin vitroprimary cell cultures represent potentially useful tools for mechanistic and preclinical investigation based upon their retention of key features of tumour subgroups under experimental conditions amenable to high-throughput approaches. We present 17 novel primary cultures derived from patients in London, Dublin and Belfast, and together with cultures established or shared from Barcelona, Brisbane, Rome and Stanford, assembled a panel of 52 models under 2D (laminin matrix) and/or 3D (neurospheres) conditions, fully credentialed by phenotypic and molecular comparison to the original tumour sample (methylation BeadArray, panel/exome sequencing, RNAseq). In screening a subset of these against a panel of ~400 approved chemotherapeutics and small molecules, we identified specific dependencies associated with tumour subgroups and/or specific molecular markers. These includedMYCN-amplified cells and ATM/DNA-PK inhibitors, and DIPGs withPPM1Dactivating truncating mutations and inhibitors of MDM2 or PARP1. Specific mutations inPDGFRAwere found to confer sensitivity to a range of RTK inhibitors, though not all such mutations conferred sensitivity to targeted agents. Notably, dual PDGFRA/FGFR and downstream pathway MEK inhibitors showed profound effects against both PDGFRA-sensitising mutant and FGFR1-dependent non-brainstem pHGG and DIPG. In total, 85% cells were found to have at least one drug screening hit in short term assays linked to the underlying biology of the patient’s tumour, providing a rational approach for individualised clinical translation.

Dear Editor, Alexander disease (AD) is a progressive degenerative leukodystrophy, which typically presents in infancy. Neonatal, juvenile and adult-onset forms of AD are relatively rare, with a more variable clinical course compared to the infantile subtype. This disorder is a consequent of de novo heterozygous missense mutations in the glial fibrillary acidic protein (GFAP) gene. Characteristic imaging findings in AD have been described in the literature and are primarily supratentorial in distribution, with a frontal predominance. We describe 2 cases of genetically confirmed juvenile-onset AD, presenting as focal tumour-like lesions within the brainstem. Magnetic resonance imaging (MRI) characteristics of these lesions are discussed, along with clues to differentiate this entity from other focal brainstem lesions within the paediatric population (such as focal glioma and demyelinating lesion). These cases highlight an atypical presentation of juvenile AD and the need for consideration of metabolic diseases when focal tumour-like brainstem lesions are encountered, thus allowing an accurate diagnosis and avoiding invasive investigation by means of tissue biopsy.

The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B ( SUV420H1 ), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments.

We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.

Intracranial germinomas are rare primary central nervous system tumours that are highly sensitive to radiotherapy and chemotherapy. Recurrences are infrequent, with the majority occurring within 5 years. Although multidisciplinary treatments have resulted in good event-free survival, long-term outcomes, over decades, are relatively poorly reported. We present a rare case of a recurrence in the conus medullaris 12 years after complete remission of the primary pituitary germinoma. To the best of our knowledge, this represents the first case of a significantly delayed spinal recurrence, occurring at a very distant and uncommon site, from the primary tumour. This case highlights the importance of long-term follow-up, even after complete remission, in order to identify and limit disability from late spinal recurrences in a relatively young patient population. We consider the literature regarding identifying high risk patients, and the role of craniospinal irradiation in limiting late spinal recurrences.

Brain abscess is an unusual complication of uncontrolled diabetes. A solitary thalamic abscess is an uncommon type of brain abscess. We report a case of thalamic abscess, whereupon diabetes mellitus and periodontitis were diagnosed. The diagnosis and management of thalamic abscess, and the interplay of type 2 diabetes and periodontitis are discussed. A 56-year-old, Caucasian, man with no medical or travel history, presented with 5-day symptoms of meningeal irritation. Body mass index 30.6 kg/m(2). CT demonstrated a solitary midline lesion with neoplasia as a differential diagnosis. It was biopsied and cultures grew Streptococcus milleri. He was treated by stereotactic puncture, external drainage and targeted intrathecal and systemic antibiotic therapy. HIV negative but glycated haemoglobin (HbA1c) 10.7% (93 mmol/mol). Dental examination revealed a small molar abscess. Radiological resolution of the thalamic abscess occurred within 2 months. Diabetes improved with 7 weeks of insulin, and maintained on metformin, HbA1c 6.9% (51 mmol/mol). There was no residual neurological disability.

Childhood tumors arising from the Sylvian fissure are extremely rare and provide not only a diagnostic imaging challenge in localization and characterization, but also complicate neurosurgical resection. Magnetic resonance imaging plays an important role in characterizing these tumors and forms an important adjunct in preoperative and perioperative neurosurgical planning. Desmoplastic infantile ganglioglioma (DIG) is a rare distinct clinico-pathologic entity with a predominantly benign prognosis that usually presents in the first 18 months of life. These tumors are invariably supratentorial in location but none have been described in the current literature to arise within the Sylvian fissure. The clinical course, imaging, and histologic/immunohistochemical features of a 3-month-old boy presenting with a Sylvian fissure DIG are described. Additionally, the authors present a literature review of DIGs and Sylvian fissure tumors. Although rare, the characteristic imaging findings of the DIG despite arising from a previously undescribed location of origin help confirm the diagnosis, resulting in a complete resection of the tumor with a favorable prognostic outcome.