PTCH1-mutant human cerebellar organoids exhibit altered neural development and recapitulate early medulloblastoma tumorigenesis.

Patched 1 (PTCH1) is the primary receptor for the sonic hedgehog (SHH) ligand and negatively regulates SHH signalling, an essential pathway in human embryogenesis. Loss-of-function mutations in PTCH1 are associated with altered neuronal development and the malignant brain tumour medulloblastoma. As a result of differences between murine and human development, molecular and cellular perturbations that arise from human PTCH1 mutations remain poorly understood. Here, we used cerebellar organoids differentiated from human induced pluripotent stem cells combined with CRISPR/Cas9 gene editing to investigate the earliest molecular and cellular consequences of PTCH1 mutations on human cerebellar development. Our findings demonstrate that developmental mechanisms in cerebellar organoids reflect in vivo processes of regionalisation and SHH signalling, and offer new insights into early pathophysiological events of medulloblastoma tumorigenesis without the use of animal models.

Visual Outcomes after Endoscopic Endonasal Transsphenoidal Resection of Pituitary Adenomas: Our Institutional Experience.

Objectives Visual dysfunction in patients with pituitary adenomas is a clear indication for endoscopic endonasal transsphenoidal surgery (EETS). However, the visual outcomes vary greatly among patients and it remains unclear what tumor, patient, and surgical characteristics contribute to postoperative visual outcomes. Methods One hundred patients with pituitary adenomas who underwent EETS between January 2011 and June 2015 in a single institution were retrospectively reviewed. General patient characteristics, pre- and postoperative visual status, clinical presentation, tumor characteristics, hormone production, radiological features, and procedural characteristics were evaluated for association with presenting visual signs and visual outcomes postoperatively. Suprasellar tumor extension (SSE) was graded 0 to 4 following a grading system as formulated by Fujimoto et al. Results Sixty-six (66/100) of all patients showed visual field defects (VFD) at the time of surgery, of whom 18% (12/66) were asymptomatic. VFD improved in 35 (35%) patients and worsened in 4 (4%) patients postoperatively. Mean visual acuity (VA) improved from 0.67 preoperatively to 0.84 postoperatively ( p = 0.04). Nonfunctioning pituitary adenomas (NFPAs) and Fujimoto grade were independent predictors of preoperative VFD in the entire cohort ( p = 0.02 and p < 0.01 respectively). A higher grade of SSE was the only factor independently associated with postoperative improvement of VFD ( p = 0.03). NFPA and Fujimoto grade 3 were independent predictors of VA improvement (both p = 0.04). Conclusion EETS significantly improved both VA and VFD for most patients, although a few patients showed deterioration of visual deficits postoperatively. Higher degrees of SSE and NFPA were independent predictors of favorable visual outcomes.

Deconstructing cerebellar development cell by cell.

The cerebellum is a pivotal centre for the integration and processing of motor and sensory information. Its extended development into the postnatal period makes this structure vulnerable to a variety of pathologies, including neoplasia. These properties have prompted intensive investigations that reveal not only developmental mechanisms in common with other regions of the neuraxis but also unique strategies to generate neuronal diversity. How the phenotypically distinct cell types of the cerebellum emerge rests on understanding how gene expression differences arise in a spatially and temporally coordinated manner from initially homogeneous cell populations. Increasingly sophisticated fate mapping approaches, culminating in genetic-induced fate mapping, have furthered the understanding of lineage relationships between early- versus later-born cells. Tracing the developmental histories of cells in this way coupled with analysis of gene expression patterns has provided insight into the developmental genetic programmes that instruct cellular heterogeneity. A limitation to date has been the bulk analysis of cells, which blurs lineage relationships and obscures gene expression differences between cells that underpin the cellular taxonomy of the cerebellum. This review emphasises recent discoveries, focusing mainly on single-cell sequencing in mouse and parallel human studies that elucidate neural progenitor developmental trajectories with unprecedented resolution. Complementary functional studies of neural repair after cerebellar injury are challenging assumptions about the stability of postnatal cellular identities. The result is a wealth of new information about the developmental mechanisms that generate cerebellar neural diversity, with implications for human evolution.

International practice variation in postoperative imaging of chronic subdural hematoma patients.

OBJECTIVE: The value of CT scanning after burr hole surgery in chronic subdural hematoma (CSDH) patients is unclear, and practice differs between countries. At the Brigham and Women's Hospital (BWH) in Boston, Massachusetts, neurosurgeons frequently order routine postoperative CT scans, while the University Medical Center Utrecht (UMCU) in the Netherlands does not have this policy. The aim of this study was to compare the use of postoperative CT scans in CSDH patients between these hospitals and to evaluate whether there are differences in clinical outcomes. METHODS: The authors collected data from both centers for 391 age- and sex-matched CSDH patients treated with burr hole surgery between January 1, 2002, and July 1, 2016, and compared the number of postoperative scans up to 6 weeks after surgery, the need for re-intervention, and postoperative neurological condition. RESULTS: BWH patients were postoperatively scanned a median of 4 times (interquartile range [IQR] 2-5), whereas UMCU patients underwent a median of 0 scans (IQR 0-1, p < 0.001). There was no significant difference in the number of re-operations (20 in the BWH vs 27 in the UMCU, p = 0.34). All re-interventions were preceded by clinical decline and no recurrences were detected on scans performed on asymptomatic patients. Patients' neurological condition was not worse in the UMCU than in the BWH (p = 0.43). CONCLUSIONS: While BWH patients underwent more scans than UMCU patients, there were no differences in clinical outcomes. The results of this study suggest that there is little benefit to routine scanning in asymptomatic patients who have undergone surgical treatment of uncomplicated CSDH and highlight opportunities to make practice more efficient.

Functional and educational outcomes after treatment for intracranial arteriovenous malformations in children.

BACKGROUND: Arteriovenous malformations (AVMs) in the pediatric population are rare, yet they form the most frequent cause of hemorrhagic stroke in children. Compared to adults, children have been suggested to have beneficial neurological outcomes. However, few studies have focused on other variables than neurological outcomes. This study aims to assess the long-term functional and educational outcomes of children after multimodality approach of treatment for intracranial AVMs. METHODS: All children treated in our center between 1998 and 2016 for intracranial AVMs were reviewed. Patient characteristics, as well as AVM specifics, were collected. Functional outcomes were compared using the modified Rankin scale (mRs). Educational levels, using the International Standard Classification of Education (ISCED), were compared to the age-matched general population of the Netherlands. RESULTS: In total, 25 children were included at mean age of 10 years (range 2-16 years). Nineteen patients (76%) presented with intracranial bleeding. Mean follow-up was 11.5 ± 5.3 years (range 4.1-24.4). Four (16%) of patients were treated with embolization, three (12%) with microsurgery, and 18 patients (72%) received a combination of different treatment modalities. Altogether, 21 (84%) were embolized, 14 (56%) were treated with microsurgery, and eight (32%) received stereotactic radiosurgery. One child had a worse mRs at discharge compared to admission; all others improved (n = 11) or were stable (n = 13). At follow-up, all patients scored a stable or improved mRs compared to discharge, with 23 children (92%) scoring mRs 0 or 1. These 23 children followed regular education during follow-up without specialized or adapted schooling. No significant differences in educational level with the age-matched general population were found. CONCLUSION: This retrospective review shows positive long-term results of both functional and educational outcomes after multidisciplinary treatment of pediatric brain AVMs.