Directed differentiation of human hindbrain neuroepithelial stem cells recapitulates cerebellar granule neurogenesis.

Cerebellar granule neurons (CGNs) are the most abundant neurons in the human brain. Dysregulation of their development underlies movement disorders and medulloblastomas. It is suspected that these disorders arise in progenitor states of the CGN lineage, for which human models are lacking. Here, we have differentiated human hindbrain neuroepithelial stem (hbNES) cells to CGNs in vitro using soluble growth factors, recapitulating key progenitor states in the lineage. We show that hbNES cells are not lineage committed and retain rhombomere 1 regional identity. Upon differentiation, hbNES cells transit through a rhombic lip (RL) progenitor state at day 7, demonstrating human specific sub-ventricular cell identities. This RL state is followed by an ATOH1+ CGN progenitor state at day 14. By the end of a 56-day differentiation procedure, we obtain functional neurons expressing CGN markers GABAARα6 and vGLUT2. We show that sonic hedgehog promotes GABAergic lineage specification and CGN progenitor proliferation. Our work presents a new model with which to study development and diseases of the CGN lineage in a human context.

Seizure outcome of pediatric magnetic resonance-guided laser interstitial thermal therapy versus open surgery: A matched noninferiority cohort study.

OBJECTIVE: Minimally invasive magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) has been proposed as an alternative to open epilepsy surgery, to address concerns regarding the risk of open surgery. Our primary hypothesis was that seizure freedom at 1 year after MRgLITT is noninferior to open surgery in children with drug-resistant epilepsy (DRE). The secondary hypothesis was that MRgLITT has fewer complications and shorter hospitalization than surgery. The primary objective was to compare seizure outcome of MRgLITT to open surgery in children with DRE. The secondary objective was to compare complications and length of hospitalization of the two treatments. METHODS: This retrospective multicenter cohort study included children with DRE treated with MRgLITT or open surgery with 1-year follow-up. Exclusion criteria were corpus callosotomy, neurostimulation, multilobar or hemispheric surgery, and lesion with maximal dimension > 60 mm. MRgLITT patients were propensity matched to open surgery patients. The primary outcome was seizure freedom at 1 year posttreatment. The difference in seizure freedom was compared using noninferiority test, with noninferiority margin of -10%. The secondary outcomes were complications and length of hospitalization. RESULTS: One hundred eighty-five MRgLITT patients were matched to 185 open surgery patients. Seizure freedom at 1 year follow-up was observed in 89 of 185 (48.1%) MRgLITT and 114 of 185 (61.6%) open surgery patients (difference = -13.5%, one-sided 97.5% confidence interval = -23.8% to ∞, pNoninferiority  = .79). The lower confidence interval boundary of -23.8% was below the prespecified noninferiority margin of -10%. Overall complications were lower in MRgLITT compared to open surgery (10.8% vs. 29.2%, respectively, p < .001). Hospitalization was shorter for MRgLITT than open surgery (3.1 ± 2.9 vs. 7.2 ± 6.1 days, p < .001). SIGNIFICANCE: Seizure outcome of MRgLITT at 1 year posttreatment was inferior to open surgery. However, MRgLITT has the advantage of better safety profile and shorter hospitalization. The findings will help counsel children and parents on the benefits and risks of MRgLITT and contribute to informed decision-making on treatment options.

Modeling SHH-driven medulloblastoma with patient iPS cell-derived neural stem cells.

Medulloblastoma is the most common malignant brain tumor in children. Here we describe a medulloblastoma model using Induced pluripotent stem (iPS) cell-derived human neuroepithelial stem (NES) cells generated from a Gorlin syndrome patient carrying a germline mutation in the sonic hedgehog (SHH) receptor PTCH1. We found that Gorlin NES cells formed tumors in mouse cerebellum mimicking human medulloblastoma. Retransplantation of tumor-isolated NES (tNES) cells resulted in accelerated tumor formation, cells with reduced growth factor dependency, enhanced neurosphere formation in vitro, and increased sensitivity to Vismodegib. Using our model, we identified LGALS1 to be a GLI target gene that is up-regulated in both Gorlin tNES cells and SHH-subgroup of medulloblastoma patients. Taken together, we demonstrate that NES cells derived from Gorlin patients can be used as a resource to model medulloblastoma initiation and progression and to identify putative targets.

Clinical predictors of survival for patients with atypical teratoid/rhabdoid tumors.

PURPOSE: Atypical teratoid/rhabdoid tumors (AT/RTs) are malignant central nervous system (CNS) neoplasms of the young. Our study analyzed a large AT/RT cohort from the National Cancer Database (NCDB) to elucidate predictors of short-term mortality and overall survival (OS). METHODS: Information was collected on patients with histologically confirmed AT/RT using the NCDB (2004-2016). Kaplan-Meier analysis indicated OS. Prognostic factors for 30-day mortality, 90-day mortality, and OS were determined via multivariate Cox proportional hazards (CPH) and logistic regression models. RESULTS: Our cohort of 189 patients had a median age of 1 year (IQR [1, 4]) and tumor size of 4.7 ± 2.0 cm at diagnosis. Seventy-two percent were under 3 years old; 55.6% were male and 71.0% were Caucasian. Fifty (27.2%) patients received only surgery (S) (OS = 5.91 months), 51 (27.7%) received surgery and chemotherapy (S + CT) (OS = 11.2 months), and 9 (4.89%) received surgery and radiotherapy (S + RT) (OS = 10.3 months). Forty-five (24.5%) received S + CT + RT combination therapy (OS = 45.4 months), 13 (17.1%) received S + CT + BMT/SCT (bone marrow or stem cell transplant) (OS = 55.5 months), and 16 (8.70%) received S + CT + RT + BMT/SCT (OS = 68.4 months). Bivariate analysis of dichotomized age (HR = 0.550, 95% CI [0.357, 0.847], p = 0.0067) demonstrated significantly increased patient survival if diagnosed at or above 1 year old. On multivariate analysis, administration of S + CT + RT, S + CT + BMT/SCT, or S + CT + RT + BMT/SCT combination therapy predicted significantly (p < 0.05) increased OS compared to surgery alone. CONCLUSION: AT/RTs are CNS tumors where those diagnosed under 1 year old have a significantly worse prognosis. Our study demonstrates that while traditional CT, RT, and BMT/SCT combination regimens prolong life, overall survival in this population is still low.

Endoscopic third ventriculostomy and choroid plexus cauterization (ETV/CPC) for hydrocephalus of infancy: a technical review.

In the twenty-first century, choroid plexus cauterization (CPC) in combination with endoscopic third ventriculostomy (ETV) has emerged as an effective treatment for some infants with hydrocephalus, leading to the favourable condition of 'shunt independence'. Herein we provide a narrative technical review considering the indications, procedural aspects, morbidity and its avoidance, postoperative care and follow-up. The CP has been the target of hydrocephalus treatment for more than a century. Early eminent neurosurgeons including Dandy, Putnam and Scarff performed CPC achieving generally poor results, and so the procedure fell out of favour. In recent years, the addition of CPC to ETV was one of the reasons greater ETV success rates were observed in Africa, compared to developed nations, and its popularity worldwide has since increased. Initial results indicate that when ETV/CPC is performed successfully, shunt independence is more likely than when ETV is undertaken alone. CPC is commonly performed using a flexible endoscope via septostomy and aims to maximally cauterize the CP. Success is more likely in infants aged >1 month, those with hydrocephalus secondary to myelomeningocele and aqueductal obstruction and those with >90% cauterized CP. Failure is more likely in those with post-haemorrhagic hydrocephalus of prematurity (PHHP), particularly those <1 month of corrected age and those with prepontine scarring. High-quality evidence comparing the efficacy of ETV/CPC with shunting is emerging, with data from ongoing and future trials offering additional promise to enhance our understanding of the true utility of ETV/CPC.

Giant choroid plexus cysts with calvarial erosion: a case report and literature review.

Choroid plexus cysts rarely grow to be symptomatic. Few large choroid plexus cysts have been reported in the pediatric population. The authors report a 15-month-old boy with increased head circumference and a bony deformity in the left parietal region due to mass effect from a giant choroid plexus cyst. The child had a craniotomy for open resection of the cyst, and made an excellent recovery. The differential diagnosis for intraventricular cysts and the literature surrounding choroid plexus cysts are discussed.

In Vitro Recapitulation of Developmental Transitions in Human Neural Stem Cells.

During nervous system development, early neuroepithelial stem (NES) cells with a highly polarized morphology and responsiveness to regionalizing morphogens give rise to radial glia (RG) cells, which generate region-specific neurons. Recently, stable neural cell populations reminiscent of NES cells have been obtained from pluripotent stem cells and the fetal human hindbrain. Here, we explore whether these cell populations, similar to their in vivo counterparts, can give rise to neural stem (NS) cells with RG-like properties and whether region-specific NS cells can be generated from NES cells with different regional identities. In vivo RG cells are thought to form from NES cells with the onset of neurogenesis. Therefore, we cultured NES cells temporarily in differentiating conditions. Upon reinitiation of growth factor treatment, cells were found to enter a developmental stage reflecting major characteristics of RG-like NS cells. These NES cell-derived NS cells exhibited a very similar morphology and marker expression as primary NS cells generated from human fetal tissue, indicating that conversion of NES cells into NS cells recapitulates the developmental progression of early NES cells into RG cells observed in vivo. Importantly, NS cells generated from NES cells with different regional identities exhibited stable region-specific transcription factor expression and generated neurons appropriate for their positional identity. Stem Cells 2019;37:1429-1440.

Stopping CSF leaks at external ventricular drain exit sites: a technical note.

PURPOSE: Cerebrospinal fluid (CSF) leak is a major risk factor for external ventricular drain infection. Here, we present a surgical technique to reduce the possibility of CSF leak at the external ventricular drain (EVD) exit site in high-risk patients. METHODS: Vertical mattress sutures are placed circumferentially around the EVD catheter tract as it passes under the skin, so to close off the tract along which CSF may travel toward the exit site. RESULTS: Specific case examples are discussed where the introduction of this technique was found to be helpful in stopping exit-site CSF leak. CONCLUSION: In our experience, these surgical steps are useful adjuncts that should be considered in all high-risk patients undergoing EVD placement.

Using Virtual Reality to investigate multitasking ability in individuals with frontal lobe lesions.

Individuals with lesions in the prefrontal cortex often show impairments with the organisation of their behaviour in everyday life. These difficulties can be hard to detect using structured formal tests. The objective of this study was to use Virtual Reality (VR) to explore the multitasking performance of individuals with focal frontal lobe lesions, specifically using the Jansari assessment of Executive Functions (JEF©). Nineteen individuals with frontal lobe lesions were compared with 19 matched controls on the test and a group of commonly used clinical measures of neuropsychological functioning, as well as questionnaire measures of everyday activity, anxiety and depression. There was a significant difference between groups on the overall JEF© score and on five of the eight individual constructs, namely the planning, creative thinking, adaptive thinking, event-based Prospective Memory (PM) and time-based PM constructs. There were no differences between groups on the non-VR EF individual measures apart from on one EF control measure, Trail Making A. These results demonstrate the potential clinical utility of the JEF© and highlight the value of ecologically valid VR measures in detecting impairments in EF in individuals with frontal lobe lesions.

Clinical audit effectively bridges the evidence-practice gap in chronic subdural haematoma management.

BACKGROUND: Placement of a subdural drain after drainage of chronic subdural haematoma (CSDH) has been shown to reduce the rate of recurrence in several randomised controlled trials (RCT). The most recently published RCT was from Cambridge, UK, in 2009. Despite class I evidence for the use of subdural drains, it is unclear whether these results have been translated into clinical practice. In this clinical audit we review the use of subdural drains in our institution before and after the publication of the 2009 RCT results. METHODS: A longitudinal retrospective study was performed on all adults having burr holes for CSDH between January 2009 and January 2014. Case notes were analysed to determine subdural drain use, re-operation for CSDH recurrence and post-operative complications. The audit loop was closed with data collected from August 2015 to January 2016. RESULTS: Thirty-one per cent of patients had subdural drains placed at operation. Drain placement was associated with lower reoperation rates (8% vs. 17%, p = 0.021) without increasing complication rates. Drain usage doubled after publication of the Santarius et al. (2009) trial but we observed persisting and significant variability in drain utilisation by supervising consultants. The use of drains in the department increased from 35% to 75% of all cases after presentation of these results. CONCLUSIONS: The use of subdural drains in our unit reduced recurrence rates following drainage of CSDH and reproduced the results of a 2009 clinical trial. Although the use of subdural drains doubled in the post-trial epoch, significant variability remains in practice. Clinical audit provided an effective tool necessary to drive the implementation of subdural drain placement in our unit.

Neonatal post-haemorrhagic hydrocephalus in the UK: a survey of current practice.

OBJECTIVES: The management of neonatal post-haemorrhagic hydrocephalus (nPHH) varies considerably between centres and even between neurosurgeons in the same centre. We performed a nationwide survey to evaluate current practice in the UK and reviewed the evidence for each intervention. METHODS: An online semi-structured questionnaire was emailed to all units registered on the British Paediatric Neurosurgery Group Mailing List. The survey consisted of 18 questions designed to establish the status quo in the management of nPHH, including preferred temporising procedure, factors guiding the timing of intervention and willingness to participate in a prospective study. RESULTS: A total of 24 consultants responded to the survey. Ventricular access device (VAD), trans-fontanelle tap, ventriculosubgaleal shunt (VSGS) and lumbar puncture (LP) were used by 33, 25, 17 and 17%, respectively, as the first temporising measure. Almost all reported that the timing of this intervention was guided by increasing head circumference and tense fontanelle. If the first temporising procedure fails, VAD, external ventricular drainage (EVD), trans-fontanelle tap, VSGS and other procedures (including ventriculoperitoneal (VP) shunting and endoscopic third ventriculostomy (ETV)) were performed by 42, 17, 13, 8 and 21%, respectively. Almost all respondents reported that VP shunting would be their preferred method of definitive cerebrospinal fluid (CSF) diversion. Almost all responded that they would be willing to participate in a prospective study in the future to determine best practice. CONCLUSION: As expected there was a significant heterogeneity between respondents in the initial management of nPHH in the UK. VAD was the most popular first and second choice temporising measure. On reviewing the literature, it is clear that more work still needs to be done to establish which temporising measure is best. There is willingness in the UK to participate in a study to help determine this.

Stem cells expanded from the human embryonic hindbrain stably retain regional specification and high neurogenic potency.

Stem cell lines that faithfully maintain the regional identity and developmental potency of progenitors in the human brain would create new opportunities in developmental neurobiology and provide a resource for generating specialized human neurons. However, to date, neural progenitor cultures derived from the human brain have either been short-lived or exhibit restricted, predominantly glial, differentiation capacity. Pluripotent stem cells are an alternative source, but to ascertain definitively the identity and fidelity of cell types generated solely in vitro is problematic. Here, we show that hindbrain neuroepithelial stem (hbNES) cells can be derived and massively expanded from early human embryos (week 5-7, Carnegie stage 15-17). These cell lines are propagated in adherent culture in the presence of EGF and FGF2 and retain progenitor characteristics, including SOX1 expression, formation of rosette-like structures, and high neurogenic capacity. They generate GABAergic, glutamatergic and, at lower frequency, serotonergic neurons. Importantly, hbNES cells stably maintain hindbrain specification and generate upper rhombic lip derivatives on exposure to bone morphogenetic protein (BMP). When grafted into neonatal rat brain, they show potential for integration into cerebellar development and produce cerebellar granule-like cells, albeit at low frequency. hbNES cells offer a new system to study human cerebellar specification and development and to model diseases of the hindbrain. They also provide a benchmark for the production of similar long-term neuroepithelial-like stem cells (lt-NES) from pluripotent cell lines. To our knowledge, hbNES cells are the first demonstration of highly expandable neuroepithelial stem cells derived from the human embryo without genetic immortalization.

Pediatric Prostatic Alveolar Rhabdomyosarcoma Presenting with Metastatic Spinal Cord Compression in the Thoracic Spine: A Case Report and Review of the Literature.

Rhabdomyosarcoma (RMS) is a pediatric malignancy with a variable prognosis depending on tumor stage and genotype. There has been a significant improvement in survival rates over the past decades. However, aggressive variants can metastasize to locations that are difficult to treat. We report a case of prostatic alveolar rhabdomyosarcoma with metastases to the bone marrow and thoracic spine in a child. The patient was treated with a multimodal approach that included surgical resection of the epidural mass; the administration of vincristine, dactinomycin, and cyclophosphamide; and radiotherapy. Unfortunately, after six months, the patient showed disease progression and was started on secondary-line treatment. This case illustrates the difficulties in managing end-stage metastatic rhabdomyosarcoma and is the first report of prostatic rhabdomyosarcoma presenting with spinal cord compression in a child.

Frameless Stereotactic Biopsy of Brainstem Tumors Using the Stealth Autoguide: A Technical Note.

BACKGROUND AND OBJECTIVES: In the molecular era of neuro-oncology, it is increasingly necessary to obtain tissue for next-generation sequencing and methylome profile for prognosis and targeted oncological management. Brainstem tumors can be technically challenging to biopsy in the pediatric population. Frame-based and frameless techniques have previously been described and proven to be safe and efficacious in children. Recent cranial robotic guidance platforms have augmented the fluency of frameless stereotactic approaches, but the technical nuances of these procedures in children are not often discussed. We present a technical workflow for frameless stereotactic biopsy of brainstem tumors in children using the Medtronic Stealth Autoguide cranial robotic guidance platform and examine safety and efficacy of this surgical approach. METHODS: A minimally invasive, frameless, transcerebellar approach is described, including operative steps and workflow. We assessed operative times, diagnostic accuracy and yield, and complication rates. RESULTS: Five patients underwent biopsy with the technique described. The youngest patient in our series was of 2 years. The intended target was achieved on postoperative imaging in all cases, and diagnostic tissue was obtained in all 5 patients. One patient had a clinically insignificant hemorrhage. CONCLUSION: Frameless stereotactic biopsy of the brainstem can be performed safely, efficiently, and accurately using the Medtronic Stealth Autoguide robotic platform in children as young as 2 years.

Machine learning models for predicting seizure outcome after MR-guided laser interstitial thermal therapy in children.

OBJECTIVE: MR-guided laser interstitial thermal therapy (MRgLITT) is associated with lower seizure-free outcome but better safety profile compared to open surgery. However, the predictors of seizure freedom following MRgLITT remain uncertain. This study aimed to use machine learning to predict seizure-free outcome following MRgLITT and to identify important predictors of seizure freedom in children with drug-resistant epilepsy. METHODS: This multicenter study included children treated with MRgLITT for drug-resistant epilepsy at 13 epilepsy centers. The authors used clinical data, diagnostic investigations, and ablation features to predict seizure-free outcome at 1 year post-MRgLITT. Patients from 12 centers formed the training cohort, and patients in the remaining center formed the testing cohort. Five machine learning algorithms were developed on the training data by using 10-fold cross-validation, and model performance was measured on the testing cohort. The models were developed and tested on the complete feature set. Subsequently, 3 feature selection methods were used to identify important predictors. The authors then assessed performance of the parsimonious models based on these important variables. RESULTS: This study included 268 patients who underwent MRgLITT, of whom 44.4% had achieved seizure freedom at 1 year post-MRgLITT. A gradient-boosting machine algorithm using the complete feature set yielded the highest area under the curve (AUC) on the testing set (AUC 0.67 [95% CI 0.50-0.82], sensitivity 0.71 [95% CI 0.47-0.88], and specificity 0.66 [95% CI 0.50-0.81]). Logistic regression, random forest, support vector machine, and neural network yielded lower AUCs (0.58-0.63) compared to the gradient-boosting machine but the findings were not statistically significant (all p > 0.05). The 3 feature selection methods identified video-EEG concordance, lesion size, preoperative seizure frequency, and number of antiseizure medications as good prognostic features for predicting seizure freedom. The parsimonious models based on important features identified by univariate feature selection slightly improved model performance compared to the complete feature set. CONCLUSIONS: Understanding the predictors of seizure freedom after MRgLITT will assist with prognostication.

Brain and Spinal Cord Tumors in Children.

This article provides general principles of managing children with central nervous system tumors. The distribution, diagnostic work-up, and key principles of treatment are reviewed, and special circumstances that may be encountered by pediatricians in the community are discussed.

Stability of ruptured intracranial aneurysms treated with detachable coils: is delayed follow-up angiography warranted?

The optimal strategy for monitoring the stability of ruptured intracranial aneurysms following coil embolisation is unclear. The value of delayed follow-up angiography in detecting new recurrences or progression of residual lesions visualised on earlier angiographic studies was determined in the light of the increasing use of non-invasive imaging techniques such as time of flight magnetic resonance angiography (TOF-MRA) for the evaluation of intracranial aneurysm occlusion. Ninety-seven patients with 105 ruptured aneurysms treated with detachable coils in 2005 and 2006 were included. The presence of a residual neck or aneurysm was assessed on catheter angiograms performed at 6 months and 2 years using the Raymond criteria (Class I = completely occluded, class II = small residual neck, class III = aneurysm sac filling). At 6-month follow-up, 32% of class I aneurysms progressed to class II and 6% of these aneurysms required re-treatment. A further 2-year angiogram was obtained in 59 patients with 65 aneurysms. Ninety-six per cent of class I, 100% of the class II and class III aneurysms remained unchanged at 2 years compared to 6 months. In our series, most recurrences were apparent at 6-month follow-up. The vast majority of coiled ruptured aneurysms that were class I or II at 6 months remained stable at 2-year follow-up. In the absence of a residual lesion in the early angiographic study, a further delayed catheter angiogram may not be warranted. The use of non-invasive strategies such as TOF-MRA should be considered.

Selective dorsal rhizotomy: an illustrated review of operative techniques.

OBJECTIVE: Selective dorsal rhizotomy (SDR) is a procedure primarily performed to improve function in a subset of children with limitations related to spasticity. There is substantial variability in operative techniques among centers and surgeons. Here, the authors provide a technical review of operative approaches for SDR. METHODS: Ovid MEDLINE, Embase, and PubMed databases were queried in accordance with PRISMA guidelines. All studies included described a novel surgical technique. The technical nuances of each approach were extracted, including extent of exposure, bone removal, and selection of appropriate nerve roots. The operative approach preferred at the authors' institution (the "2 × 3 exposure") is also detailed. RESULTS: Five full-text papers were identified from a total of 380 articles. Operative approaches to SDR varied significantly with regard to level of exposure, extent of laminectomy, and identification of nerve roots. The largest exposure involved a multilevel laminectomy, while the smallest exposure involved a keyhole interlaminar approach. At the Hospital for Sick Children, the authors utilize a two-level laminoplasty at the level of the conus medullaris. The benefits and disadvantages of the spectrum of techniques are discussed, and illustrative figures are provided. CONCLUSIONS: Surgical approaches to SDR vary considerably and are detailed and illustrated in this review as a guide for neurosurgeons. Future studies should address the long-term impact of these techniques on functional outcomes and complications such as spinal deformity.