Chromatin remodeller Chd7 is developmentally regulated in the neural crest by tissue-specific transcription factors.

Neurocristopathies such as CHARGE syndrome result from aberrant neural crest development. A large proportion of CHARGE cases are attributed to pathogenic variants in the gene encoding CHD7, chromodomain helicase DNA binding protein 7, which remodels chromatin. While the role for CHD7 in neural crest development is well documented, how this factor is specifically up-regulated in neural crest cells is not understood. Here, we use epigenomic profiling of chick and human neural crest to identify a cohort of enhancers regulating Chd7 expression in neural crest cells and other tissues. We functionally validate upstream transcription factor binding at candidate enhancers, revealing novel epistatic relationships between neural crest master regulators and Chd7, showing tissue-specific regulation of a globally acting chromatin remodeller. Furthermore, we find conserved enhancer features in human embryonic epigenomic data and validate the activity of the human equivalent CHD7 enhancers in the chick embryo. Our findings embed Chd7 in the neural crest gene regulatory network and offer potentially clinically relevant elements for interpreting CHARGE syndrome cases without causative allocation.

The SWI/SNF Complex in Neural Crest Cell Development and Disease.

While the neural crest cell population gives rise to an extraordinary array of derivatives, including elements of the craniofacial skeleton, skin pigmentation, and peripheral nervous system, it is today increasingly recognized that Schwann cell precursors are also multipotent. Two mammalian paralogs of the SWI/SNF (switch/sucrose nonfermentable) chromatin-remodeling complexes, BAF (Brg1-associated factors) and PBAF (polybromo-associated BAF), are critical for neural crest specification during normal mammalian development. There is increasing evidence that pathogenic variants in components of the BAF and PBAF complexes play central roles in the pathogenesis of neural crest-derived tumors. Transgenic mouse models demonstrate a temporal window early in development where pathogenic variants in Smarcb1 result in the formation of aggressive, poorly differentiated tumors, such as rhabdoid tumors. By contrast, later in development, homozygous inactivation of Smarcb1 requires additional pathogenic variants in tumor suppressor genes to drive the development of differentiated adult neoplasms derived from the neural crest, which have a comparatively good prognosis in humans.

Metastatic meningioma: a case series and systematic review.

BACKGROUND: Meningiomas are the most common primary intracranial tumor. While the majority of meningiomas are benign, rarely they can metastasize extracranially. There is a need for a more comprehensive review of these patients to improve our understanding of this rare phenomenon and its prevalence globally. Here we describe our institution's experience of patients presenting with metastatic meningiomas. We further perform a systematic review of the existing literature to explore common features of this rare manifestation of meningioma and review the efficacy of current treatments. METHODS: We performed a retrospective clinical review of all adult patients with metastatic meningioma managed at our institution over the past 20 years, identifying 6 patients. We then performed a systematic review of cases of metastatic meningioma in the literature ranging from the years 1886 to 2022. A descriptive analysis was then conducted on the available data from 1979 onward, focusing on the grade and location of the primary tumor as well as the latency period to, and location of, the metastasis. RESULTS: In total, we analyzed 155 cases. Fifty-four percent of patients initially presented with a primary meningioma located in the convexity. The most common site of metastasis was the lung. Risk factors associated with a shorter time to metastasis were male sex and a high initial grade of the tumor. Regarding treatment, the addition of chemotherapy was the most common adjunct to the standard management of surgery and radiotherapy. Despite an exhaustive review we were unable to identify effective treatments. The majority of published cases came from centers situated in high-income countries (84%) while only 16% came from lower- and middle-income countries. CONCLUSIONS: Metastatic meningiomas pose a pertinent, and likely underestimated, clinical challenge within modern neurosurgery. To optimize management, timely identification of these patients is important. More research is needed to explore the mechanisms underlying these tumors to better guide the development of effective screening and management protocols. However, screening of each meningioma patient is not feasible, and at the heart of this challenge is the inability to control the primary disease. Ultimately, a consensus is needed as to how to correctly screen for and manage these patients; genomic and epigenomic approaches could hold the answer to finding druggable targets.

Intraoperative imaging technology to maximise extent of resection for glioma: a network meta-analysis.

BACKGROUND: Multiple studies have identified the prognostic relevance of extent of resection in the management of glioma. Different intraoperative technologies have emerged in recent years with unknown comparative efficacy in optimising extent of resection. One previous Cochrane Review provided low- to very low-certainty evidence in single trial analyses and synthesis of results was not possible. The role of intraoperative technology in maximising extent of resection remains uncertain. Due to the multiple complementary technologies available, this research question is amenable to a network meta-analysis methodological approach. OBJECTIVES: To establish the comparative effectiveness and risk profile of specific intraoperative imaging technologies using a network meta-analysis and to identify cost analyses and economic evaluations as part of a brief economic commentary. SEARCH METHODS: We searched CENTRAL (2020, Issue 5), MEDLINE via Ovid to May week 2 2020, and Embase via Ovid to 2020 week 20. We performed backward searching of all identified studies. We handsearched two journals, Neuro-oncology and the Journal of Neuro-oncology from 1990 to 2019 including all conference abstracts. Finally, we contacted recognised experts in neuro-oncology to identify any additional eligible studies and acquire information on ongoing randomised controlled trials (RCTs). SELECTION CRITERIA: RCTs evaluating people of all ages with presumed new or recurrent glial tumours (of any location or histology) from clinical examination and imaging (computed tomography (CT) or magnetic resonance imaging (MRI), or both). Additional imaging modalities (e.g. positron emission tomography, magnetic resonance spectroscopy) were not mandatory. Interventions included fluorescence-guided surgery, intraoperative ultrasound, neuronavigation (with or without additional image processing, e.g. tractography), and intraoperative MRI. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the search results for relevance, undertook critical appraisal according to known guidelines, and extracted data using a prespecified pro forma. MAIN RESULTS: We identified four RCTs, using different intraoperative imaging technologies: intraoperative magnetic resonance imaging (iMRI) (2 trials, with 58 and 14 participants); fluorescence-guided surgery with 5-aminolevulinic acid (5-ALA) (1 trial, 322 participants); and neuronavigation (1 trial, 45 participants). We identified one ongoing trial assessing iMRI with a planned sample size of 304 participants for which results are expected to be published around winter 2020. We identified no published trials for intraoperative ultrasound. Network meta-analyses or traditional meta-analyses were not appropriate due to absence of homogeneous trials across imaging technologies. Of the included trials, there was notable heterogeneity in tumour location and imaging technologies utilised in control arms. There were significant concerns regarding risk of bias in all the included studies. One trial of iMRI found increased extent of resection (risk ratio (RR) for incomplete resection was 0.13, 95% confidence interval (CI) 0.02 to 0.96; 49 participants; very low-certainty evidence) and one trial of 5-ALA (RR for incomplete resection was 0.55, 95% CI 0.42 to 0.71; 270 participants; low-certainty evidence). The other trial assessing iMRI was stopped early after an unplanned interim analysis including 14 participants; therefore, the trial provided very low-quality evidence. The trial of neuronavigation provided insufficient data to evaluate the effects on extent of resection. Reporting of adverse events was incomplete and suggestive of significant reporting bias (very low-certainty evidence). Overall, the proportion of reported events was low in most trials and, therefore, issues with power to detect differences in outcomes that may or may not have been present. Survival outcomes were not adequately reported, although one trial reported no evidence of improvement in overall survival with 5-ALA (hazard ratio (HR) 0.82, 95% CI 0.62 to 1.07; 270 participants; low-certainty evidence). Data for quality of life were only available for one study and there was significant attrition bias (very low-certainty evidence). AUTHORS' CONCLUSIONS: Intraoperative imaging technologies, specifically 5-ALA and iMRI, may be of benefit in maximising extent of resection in participants with high-grade glioma. However, this is based on low- to very low-certainty evidence. Therefore, the short- and long-term neurological effects are uncertain. Effects of image-guided surgery on overall survival, progression-free survival, and quality of life are unclear. Network and traditional meta-analyses were not possible due to the identified high risk of bias, heterogeneity, and small trials included in this review. A brief economic commentary found limited economic evidence for the equivocal use of iMRI compared with conventional surgery. In terms of costs, one non-systematic review of economic studies suggested that, compared with standard surgery, use of image-guided surgery has an uncertain effect on costs and that 5-ALA was more costly. Further research, including completion of ongoing trials of ultrasound-guided surgery, is needed.

ANTECEDENTES: En múltiples estudios se ha identificado la importancia pronóstica del alcance de la resección en el tratamiento del glioma. En los últimos años han surgido diferentes tecnologías intraoperatorias con una eficacia comparativa desconocida para optimizar el alcance de la resección. Una revisión Cochrane anterior proporcionó evidencia de certeza baja a muy baja en los análisis de un solo ensayo y no fue posible la síntesis de los resultados. La función de la tecnología intraoperatoria para maximizar el alcance de la resección aún no está clara. Debido a las múltiples tecnologías complementarias disponibles, esta pregunta de investigación se presta a un enfoque metodológico de metanálisis en red. OBJETIVOS: Establecer el perfil comparativo de efectividad y riesgo de determinadas tecnologías de imagenología intraoperatorias mediante un metanálisis en red e identificar análisis de costos y evaluaciones económicas como parte de un breve comentario económico. MÉTODOS DE BÚSQUEDA: Se hicieron búsquedas en CENTRAL (2020, número 5), MEDLINE vía Ovid hasta la semana 2 de mayo de 2020, y Embase vía Ovid hasta la semana 20 de 2020. Se realizó una búsqueda retrospectiva de todos los estudios identificados. Se hicieron búsquedas manuales en dos revistas, Neuro­oncology y Journal of Neuro­oncology, desde 1990 hasta 2019, y se incluyeron todos los resúmenes de congresos. Finalmente, se estableció contacto con expertos reconocidos en neurooncología para identificar cualquier estudio elegible adicional y obtener información sobre los ensayos controlados aleatorizados (ECA) en curso. CRITERIOS DE SELECCIÓN: ECA que evaluaron a personas de todas las edades con presuntos tumores gliales nuevos o recidivantes (de cualquier ubicación o histología) a partir del examen clínico y la imagenología (tomografía computarizada [TC] o imagenología de resonancia magnética [IRM], o ambas). Las modalidades adicionales de imagenología (p.ej., tomografía de emisión de positrones, espectroscopia de resonancia magnética) no fueron obligatorias. Las intervenciones incluyeron cirugía guiada por fluorescencia, ecografía intraoperatoria, neuronavegación (con o sin procesamiento adicional de las imágenes, p.ej., tractografía) e IRM intraoperatoria. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión, de forma independiente, evaluaron los resultados de la búsqueda en cuanto a su relevancia, realizaron la evaluación crítica según las guías conocidas y extrajeron los datos mediante un formulario predeterminado. RESULTADOS PRINCIPALES: Se identificaron cuatro ECA, que utilizaron diferentes tecnologías de imagenología intraoperatorias: la resonancia magnética (IRM) intraoperatoria (dos ensayos, con 58 y 14 participantes); la cirugía guiada por fluorescencia con ácido 5­aminolevulínico (5­ALA) (un ensayo, 322 participantes); y la neuronavegación (un ensayo, 45 participantes). Se identificó un ensayo en curso que evaluó la IRM con un tamaño de la muestra planificado de 304 participantes, del que se espera la publicación de los resultados alrededor del invierno de 2020. No se han identificado ensayos publicados sobre la ecografía intraoperatoria. Los metanálisis en red o los metanálisis tradicionales no fueron apropiados debido a la falta de ensayos homogéneos en tecnologías de imagenología. De los ensayos incluidos, hubo una notable heterogeneidad en la localización de los tumores y en las tecnologías de imagenología utilizadas en los brazos control. Hubo inquietudes significativas con respecto al riesgo de sesgo en todos los estudios incluidos. Un ensayo de IRM encontró un aumento en la extensión de la resección (razón de riesgos [RR] para la resección incompleta 0,13; intervalo de confianza [IC] del 95%: 0,02 a 0,96; 49 participantes; evidencia de certeza muy baja) y un ensayo de 5­ALA (RR para la resección incompleta 0,55; IC del 95%: 0,42 a 0,71; 270 participantes; evidencia de certeza baja). El otro ensayo que evaluó la IRM se interrumpió de forma temprana después de un análisis intermedio no planificado que incluyó 14 participantes; por lo tanto, el ensayo proporciona evidencia de calidad muy baja. El ensayo de neuronavegación no proporcionó datos suficientes para evaluar los efectos sobre el grado de resección. El informe de los eventos adversos fue incompleto e indicó la presencia de sesgo de informe significativo (evidencia de certeza muy baja). En general, la proporción de eventos informados fue baja en la mayoría de los ensayos y, por lo tanto, pueden haber estado presentes o no problemas relacionados con el poder estadístico suficiente para detectar diferencias en los desenlaces. No se informó adecuadamente sobre los desenlaces de supervivencia, aunque un ensayo no informó evidencia de mejora en la supervivencia general con 5­ALA (cociente de riesgos instantáneos [CRI] 0,82; IC del 95%: 0,62 a 1,07; 270 participantes; evidencia de certeza baja). Solo hubo datos disponibles sobre la calidad de vida de un estudio, con un sesgo de desgaste significativo (evidencia de certeza muy baja). CONCLUSIONES DE LOS AUTORES: Las tecnologías de imagenología intraoperatoria, específicamente la IRM y el 5­ALA, pueden ser beneficiosas para maximizar el grado de resección en los participantes con glioma de grado alto. Sin embargo, lo anterior se basa en evidencia de certeza baja a muy baja. Por lo tanto, los efectos neurológicos a corto y a largo plazo no están claros. No están claros los efectos de la cirugía guiada por imágenes sobre la supervivencia general, la supervivencia sin progresión ni la calidad de vida. No fue posible realizar metanálisis en red ni tradicionales debido al alto riesgo de sesgo identificado, a la heterogeneidad y a los ensayos pequeños incluidos en esta revisión. Un comentario económico breve encontró evidencia económica limitada sobre el uso equívoco de la IRM en comparación con la cirugía convencional. En cuanto a los costos, una revisión no sistemática de estudios económicos indicó que, en comparación con la cirugía estándar, el uso de la cirugía guiada por imágenes no tiene un efecto claro sobre los costos y que el ácido 5­aminolevulínico fue más costoso. Se necesitan estudios de investigación adicionales, incluida la finalización de los ensayos en curso sobre la cirugía guiada por ecografía.

Neurosurgery activity levels in the United Kingdom and republic of Ireland during the first wave of the covid-19 pandemic - a retrospective cross-sectional cohort study.

The impact of Covid-19 on surgical patients worldwide has been substantial. In the United Kingdom (UK) and the Republic of Ireland (RoI), the first wave of the pandemic occurred in March 2020. The aims of this study were to: (1) evaluate the volume of neurosurgical operative activity levels, Covid-19 infection rate and mortality rate in April 2020 with a retrospective cross-sectional cohort study conducted across 16 UK and RoI neurosurgical centres, and (2) compare patient outcomes in a single institution in April-June 2020 with a comparative cohort in 2019. Across the UK and RoI, 818 patients were included. There were 594 emergency and 224 elective operations. The incidence rate of Covid-19 infection was 2.6% (21/818). The overall mortality rate in patients with a Covid-19 infection was 28.6% (6/21). In the single centre cohort analysis, an overall reduction in neurosurgical operative activity by 65% was observed between 2020 (n = 304) and 2019 (n = 868). The current and future impact on UK neurosurgical operative activity has implications for service delivery and neurosurgical training.

CSF rhinorrhoea after endonasal intervention to the anterior skull base (CRANIAL): proposal for a prospective multicentre observational cohort study.

BACKGROUND: The endonasal transsphenoidal approach (TSA) has emerged as the preferred approach in order to treat pituitary adenoma and related sellar pathologies. The recently adopted expanded endonasal approach (EEA) has improved access to the ventral skull base whilst retaining the principles of minimally invasive surgery. Despite the advantages these approaches offer, cerebrospinal fluid (CSF) rhinorrhoea remains a common complication. There is currently a lack of comparative evidence to guide the best choice of skull base reconstruction, resulting in considerable heterogeneity of current practice. This study aims to determine: (1) the scope of the methods of skull base repair; and (2) the corresponding rates of postoperative CSF rhinorrhoea in contemporary neurosurgical practice in the UK and Ireland. METHODS: We will adopt a multicentre, prospective, observational cohort design. All neurosurgical units in the UK and Ireland performing the relevant surgeries (TSA and EEA) will be eligible to participate. Eligible cases will be prospectively recruited over 6 months with 6 months of postoperative follow-up. Data points collected will include: demographics, tumour characteristics, operative data), and postoperative outcomes. Primary outcomes include skull base repair technique and CSF rhinorrhoea (biochemically confirmed and/or requiring intervention) rates. Pooled data will be analysed using descriptive statistics. All skull base repair methods used and CSF leak rates for TSA and EEA will be compared against rates listed in the literature. ETHICS AND DISSEMINATION: Formal institutional ethical board review was not required owing to the nature of the study - this was confirmed with the Health Research Authority, UK. CONCLUSIONS: The need for this multicentre, prospective, observational study is highlighted by the relative paucity of literature and the resultant lack of consensus on the topic. It is hoped that the results will give insight into contemporary practice in the UK and Ireland and will inform future studies.

The use of an electronic health record system reduces errors in the National Hip Fracture Database.

AIM: to compare the validity of data submitted from a UK level 1 trauma centre to the National Hip Fracture Database (NHFD) before and after the introduction of an electronic health record system (EHRS). PATIENTS AND METHODS: a total of 3224 records were reviewed from July 2009 to July 2017. 2,133 were submitted between July 2009 and October 2014 and 1,091 between October 2014 and July 2017, representing data submitted before and after the introduction of the EHRS, respectively. Data submitted to the NHFD were scrutinised against locally held data. RESULTS: use of an EHRS was associated with significant reductions in NHFD errors. The operation coding error rate fell significantly from 23.2% (494/2133) to 7.6% (83/1091); P < 0.001. Prior to EHRS introduction, of the 109 deaths recorded in the NHFD, 64 (59%) were incorrect. In the EHRS dataset, all the 112 recorded deaths were correct (P < 0.001). There was no significant difference in the error rate for fracture coding. In the EHRS dataset, after controlling for sample month, entries utilising an operation note template with mandatory fields relevant to NHFD data were more likely to be error free than those not using the template (OR 2.69; 95% CI 1.92-3.78). CONCLUSION: this study highlights a potential benefit of EHR systems, which offer automated data collection for auditing purposes. However, errors in data submitted to the NHFD remain, particularly in cases where an NHFD-specific operation note template is not used. Clinician engagement with new technologies is vital to avoid human error and ensure database integrity.

Evaluation of nationwide referral pathways, investigation and treatment of suspected cauda equina syndrome in the United Kingdom.

Purpose: Cauda equina syndrome (CES) is a spinal emergency with clinical symptoms and signs that have low diagnostic accuracy. National guidelines in the United Kingdom (UK) state that all patients should undergo an MRI prior to referral to specialist spinal units and surgery should be performed at the earliest opportunity. We aimed to evaluate the current practice of investigating and treating suspected CES in the UK. Materials and Methods: A retrospective, multicentre observational study of the investigation and management of patients with suspected CES was conducted across the UK, including all patients referred to a spinal unit over 6 months between 1st October 2016 and 31st March 2017. Results: A total of 28 UK spinal units submitted data on 4441 referrals. Over half of referrals were made without any previous imaging (n = 2572, 57.9%). Of all referrals, 695 underwent surgical decompression (15.6%). The majority of referrals were made out-of-hours (n = 2229/3517, 63.4%). Patient location and pre-referral imaging were not associated with time intervals from symptom onset or presentation to decompression. Patients investigated outside of the spinal unit experienced longer time intervals from referral to undergoing the MRI scan. Conclusions: This is the largest known study of the investigation and management of suspected CES. We found that the majority of referrals were made without adequate investigations. Most patients were referred out-of-hours and many were transferred for an MRI without subsequently requiring surgery. Adherence to guidelines would reduce the number of referrals to spinal services by 72% and reduce the number of patient transfers by 79%.

Magnetic resonance perfusion for differentiating low-grade from high-grade gliomas at first presentation.

BACKGROUND: Gliomas are the most common primary brain tumour. They are graded using the WHO classification system, with Grade II-IV astrocytomas, oligodendrogliomas and oligoastrocytomas. Low-grade gliomas (LGGs) are WHO Grade II infiltrative brain tumours that typically appear solid and non-enhancing on magnetic resonance imaging (MRI) scans. People with LGG often have little or no neurologic deficit, so may opt for a watch-and-wait-approach over surgical resection, radiotherapy or both, as surgery can result in early neurologic disability. Occasionally, high-grade gliomas (HGGs, WHO Grade III and IV) may have the same MRI appearance as LGGs. Taking a watch-and-wait approach could be detrimental for the patient if the tumour progresses quickly. Advanced imaging techniques are increasingly used in clinical practice to predict the grade of the tumour and to aid clinical decision of when to intervene surgically. One such advanced imaging technique is magnetic resonance (MR) perfusion, which detects abnormal haemodynamic changes related to increased angiogenesis and vascular permeability, or "leakiness" that occur with aggressive tumour histology. These are reflected by changes in cerebral blood volume (CBV) expressed as rCBV (ratio of tumoural CBV to normal appearing white matter CBV) and permeability, measured by Ktrans. OBJECTIVES: To determine the diagnostic test accuracy of MR perfusion for identifying patients with primary solid and non-enhancing LGGs (WHO Grade II) at first presentation in children and adults. In performing the quantitative analysis for this review, patients with LGGs were considered disease positive while patients with HGGs were considered disease negative.To determine what clinical features and methodological features affect the accuracy of MR perfusion. SEARCH METHODS: Our search strategy used two concepts: (1) glioma and the various histologies of interest, and (2) MR perfusion. We used structured search strategies appropriate for each database searched, which included: MEDLINE (Ovid SP), Embase (Ovid SP), and Web of Science Core Collection (Science Citation Index Expanded and Conference Proceedings Citation Index). The most recent search for this review was run on 9 November 2016.We also identified 'grey literature' from online records of conference proceedings from the American College of Radiology, European Society of Radiology, American Society of Neuroradiology and European Society of Neuroradiology in the last 20 years. SELECTION CRITERIA: The titles and abstracts from the search results were screened to obtain full-text articles for inclusion or exclusion. We contacted authors to clarify or obtain missing/unpublished data.We included cross-sectional studies that performed dynamic susceptibility (DSC) or dynamic contrast-enhanced (DCE) MR perfusion or both of untreated LGGs and HGGs, and where rCBV and/or Ktrans values were reported. We selected participants with solid and non-enhancing gliomas who underwent MR perfusion within two months prior to histological confirmation. We excluded studies on participants who received radiation or chemotherapy before MR perfusion, or those without histologic confirmation. DATA COLLECTION AND ANALYSIS: Two review authors extracted information on study characteristics and data, and assessed the methodological quality using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. We present a summary of the study characteristics and QUADAS-2 results, and rate studies as good quality when they have low risk of bias in the domains of reference standard of tissue diagnosis and flow and timing between MR perfusion and tissue diagnosis.In the quantitative analysis, LGGs were considered disease positive, while HGGs were disease negative. The sensitivity refers to the proportion of LGGs detected by MR perfusion, and specificity as the proportion of detected HGGs. We constructed two-by-two tables with true positives and false negatives as the number of correctly and incorrectly diagnosed LGG, respectively, while true negatives and false positives are the number of correctly and incorrectly diagnosed HGG, respectively.Meta-analysis was performed on studies with two-by-two tables, with further sensitivity analysis using good quality studies. Limited data precluded regression analysis to explore heterogeneity but subgroup analysis was performed on tumour histology groups. MAIN RESULTS: Seven studies with small sample sizes (4 to 48) met our inclusion criteria. These were mostly conducted in university hospitals and mostly recruited adult patients. All studies performed DSC MR perfusion and described heterogeneous acquisition and post-processing methods. Only one study performed DCE MR perfusion, precluding quantitative analysis.Using patient-level data allowed selection of individual participants relevant to the review, with generally low risks of bias for the participant selection, reference standard and flow and timing domains. Most studies did not use a pre-specified threshold, which was considered a significant source of bias, however this did not affect quantitative analysis as we adopted a common rCBV threshold of 1.75 for the review. Concerns regarding applicability were low.From published and unpublished data, 115 participants were selected and included in the meta-analysis. Average rCBV (range) of 83 LGGs and 32 HGGs were 1.29 (0.01 to 5.10) and 1.89 (0.30 to 6.51), respectively. Using the widely accepted rCBV threshold of <1.75 to differentiate LGG from HGG, the summary sensitivity/specificity estimates were 0.83 (95% CI 0.66 to 0.93)/0.48 (95% CI 0.09 to 0.90). Sensitivity analysis using five good quality studies yielded sensitivity/specificity of 0.80 (95% CI 0.61 to 0.91)/0.67 (95% CI 0.07 to 0.98). Subgroup analysis for tumour histology showed sensitivity/specificity of 0.92 (95% CI 0.55 to 0.99)/0.42 (95% CI 0.02 to 0.95) in astrocytomas (6 studies, 55 participants) and 0.77 (95% CI 0.46 to 0.93)/0.53 (95% CI 0.14 to 0.88) in oligodendrogliomas+oligoastrocytomas (6 studies, 56 participants). Data were too sparse to investigate any differences across subgroups. AUTHORS' CONCLUSIONS: The limited available evidence precludes reliable estimation of the performance of DSC MR perfusion-derived rCBV for the identification of grade in untreated solid and non-enhancing LGG from that of HGG. Pooled data yielded a wide range of estimates for both sensitivity (range 66% to 93% for detection of LGGs) and specificity (range 9% to 90% for detection of HGGs). Other clinical and methodological features affecting accuracy of the technique could not be determined from the limited data. A larger sample size of both LGG and HGG, preferably using a standardised scanning approach and with an updated reference standard incorporating molecular profiles, is required for a definite conclusion.

Survival Trends After Surgery for Acute Subdural Hematoma in Adults Over a 20-year Period.

OBJECTIVE: We sought to determine 30-day survival trends and prognostic factors following surgery for acute subdural hematomas (ASDHs) in England and Wales over a 20-year period. SUMMARY OF BACKGROUND DATA: ASDHs are still considered the most lethal type of traumatic brain injury. It remains unclear whether the adjusted odds of survival have improved significantly over time. METHODS: Using the Trauma Audit and Research Network (TARN) database, we analyzed ASDH cases in the adult population (>16 yrs) treated surgically between 1994 and 2013. Two thousand four hundred ninety-eight eligible cases were identified. Univariable and multiple logistic regression analyses were performed, using multiple imputation for missing data. RESULTS: The cohort was 74% male with a median age of 48.9 years. Over half of patients were comatose at presentation (53%). Mechanism of injury was due to a fall (<2 m 34%, >2 m 24%), road traffic collision (25%), and other (17%). Thirty-six per cent of patients presented with polytrauma. Gross survival increased from 59% in 1994 to 1998 to 73% in 2009 to 2013. Under multivariable analysis, variables independently associated with survival were year of injury, Glasgow Coma Scale, Injury Severity Score, age, and pupil reactivity. The time interval from injury to craniotomy and direct admission to a neurosurgical unit were not found to be significant prognostic factors. CONCLUSIONS: A significant improvement in survival over the last 20 years was observed after controlling for multiple prognostic factors. Prospective trials and cohort studies are expected to elucidate the distribution of functional outcome in survivors.

Do Patients Taking Warfarin Experience Delays to Theatre, Longer Hospital Stay, and Poorer Survival After Hip Fracture?

BACKGROUND: Patients sustaining a fractured neck of the femur are typically of advanced age with multiple comorbidities. As a consequence, the proportion of these patients receiving warfarin therapy is approximately 10%. There are currently few studies investigating outcomes in this subset of patients. QUESTIONS/PURPOSES: The purpose of this study was to assess the association between warfarin therapy and time to surgery, length of hospital stay, and survival in patients sustaining a fractured neck of the femur. METHODS: Data for 2036 patients admitted to our center between July 2009 and July 2014 with a fractured neck of the femur were extracted from the National Hip Fracture Database. Fifty-seven patients received no surgical treatment and were excluded from analysis. Multivariable ordinary least squares regression was performed to test the association between warfarin treatment on time to surgery and length of stay, and Cox proportional hazards to test followup survival. Variables included in the regression model were age, sex, American Society of Anesthesiologists (ASA) score, admission Abbreviated Mental Test Score (AMTS), fracture type, operation type, and premorbid Work Ability Index (WAI). One hundred fifty-two of 1979 surgically treated patients (8%) were receiving warfarin therapy at the time of admission. RESULTS: After controlling for age, sex, ASA score, AMTS, fracture type, operation type, and WAI, we found that patients taking warfarin were less likely to go to surgery by 36 hours (odds ratio [OR], 0.20; 95% CI, 0.14-0.30), and less likely to go to surgery by 48 hours (OR, 0.17; 95% CI, 0.11-0.24). Patients taking warfarin had a longer length of stay (median, 15 days; interquartile range [IQR], 12-22 days) compared with patients not taking warfarin (median, 13 days; IQR, 9-20 days; p < 0.001). Survival analysis to June 2015 showed a higher mortality for patients taking warfarin (12-month survival, 66% vs 76%; hazard ratio, 1.57; 95% CI, 1.21-2.04; p < 0.001). CONCLUSIONS: After controlling for multiple prognostic factors such as age, ASA score, AMTS, and WAI, warfarin therapy at the time of injury is associated with increased time to surgery, length of stay, and decreased survival. This study highlights the need to view warfarin therapy as a 'red flag' in patients presenting with a fractured neck of the femur. Preoperatively, prompt warfarin reversal together with adequate investigation and optimization of the patient should ensure timely, safe surgery. Early involvement of the anesthesia team should ensure an appropriate level of postoperative care for these patients. LEVEL OF EVIDENCE: Level III, therapeutic study.

Volumetric growth rates of meningioma and its correlation with histological diagnosis and clinical outcome: a systematic review.

INTRODUCTION: Tumour growth has been used to successfully predict progression-free survival in low-grade glioma. This systematic review sought to establish the evidence base regarding the correlation of volumetric growth rates with histological diagnosis and potential to predict clinical outcome in patients with meningioma. METHODS: This systematic review was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Databases were searched for full text English articles analysing volumetric growth rates in patients with a meningioma. RESULTS: Four retrospective cohort studies were accepted, demonstrating limited evidence of significantly different tumour doubling rates and shapes of growth curves between benign and atypical meningiomas. Heterogeneity of patient characteristics and timing of volumetric assessment, both pre- and post-operatively, limited pooled analysis of the data. No studies performed statistical analysis to demonstrate the clinical utility of growth rates in predicting clinical outcome. CONCLUSION: This systematic review provides limited evidence in support of the use of volumetric growth rates in meningioma to predict histological diagnosis and clinical outcome to guide future monitoring and treatment.

Correlation of volumetric growth and histological grade in 50 meningiomas.

INTRODUCTION: Advances in radiological imaging techniques have enabled volumetric measurements of meningiomas to be easily monitored using serial imaging scans. There is limited literature on the relationship between tumour growth rates and the WHO classification of meningiomas despite tumour growth being a major determinant of type and timing of intervention. Volumetric growth has been successfully used to assess growth of low-grade glioma; however, there is limited information on the volumetric growth rate (VGR) of meningiomas. This study aimed to determine the reliability of VGR measurement in patients with meningioma, assess the relationship between VGR and 2016 WHO grading as well as clinical applicability of VGR in monitoring meningioma growth. METHODS: All histologically proven intracranial meningiomas that underwent resection in a single centre between April 2009 and April 2014 were reviewed and classified according to the 2016 edition of the Classification of the Tumours of the CNS. Only patients who had two pre-operative scans that were at least 3 months apart were included in the study. Two authors performed the volumetric measurements using the Slicer 3D software independently and the inter-rater reliability was assessed. Multiple regression analyses of factors affecting the VGR and VDE of meningiomas were performed using the R statistical software with p < 0.05 considered to be statistically significant. RESULTS: Of 548 patients who underwent resection of their meningiomas, 66 met the inclusion criteria. Sixteen cases met the exclusion criteria (NF2, spinal location, previous surgical or radiation treatment, significant intra-osseous component and poor quality imaging). Forty-two grade I and 8 grade II meningiomas were included in the analysis. The VGR was significantly higher for grade II meningiomas. Using receiver-operator characteristic (ROC) curve analysis, the optimal threshold that distinguishes between grade I and II meningiomas is 3 cm3/year. Higher histological grade, high initial tumour volume, MRI T2-signal hyperintensity and presence of oedema were found to be significant predictors of higher VGR. CONCLUSION: Reliable tools now exist to evaluate and monitor volumetric growth of meningiomas. Grade II meningiomas have significantly higher VGR compared with grade I meningiomas and growth of more than 3 cm3/year is strongly suggestive of a higher grade meningioma. A larger, multi-centre prospective study to investigate the applicability of velocity of growth to predict the outcome of patients with meningioma is warranted.

Launching an SBNS-accredited neurosurgical skills workshop for medical students and foundation trainees.

The Neurology and Neurosurgery Interest Group (NANSIG), the student arm of the Society of British Neurological Surgeons (SBNS), organised a neurosurgical skills workshop in January 2017 following evidence of high demand among medical students and foundation trainees. The workshop involved ten delegates and five neurosurgical trainees with one senior consultant. Modules covering head positioning, burr holes, ventricular access, and flaps were included. This 'Introduction to Neurosurgery' skills workshop demonstrated significantly improved knowledge and confidence of delegates with attending and assisting in theatre in the future.

The financial outcome of traumatic brain injury: a single centre study.

OBJECTIVES: Severe traumatic brain injury (TBI) is a potentially devastating insult to the brain with high rates of fatality and neurological deficits. TBI can result in substantial costs to the centre providing care. We sought to present the experience of a Major Trauma Centre (MTC) and ascertain the financial implications of this healthcare provision, in particular detailed costs, reimbursement and the surplus or deficit accrued by the centre. DESIGN: All cranial non-elective neurosurgical admissions with a TBI over 4.5 months (26 October 2014 to 15 March 2015) were analysed retrospectively, excluding cases of chronic subdural haematoma, at an MTC in England. Demographic data were collected alongside detailed cost and income data. RESULTS: Ninety four patients were identified. The majority of patients presented with more than one diagnosis of cranial trauma. Average length of stay was 18.8 ± 21.6 days. Total deficits as a result of treating this cohort amounted to £558,034. There was a significant association between (i) more complex presentations and (ii) a longer length of stay and the deficit accrued by the centre. The major drivers of the financial outcome were costs associated with wards, medical staffing and overheads. CONCLUSION: There was a substantial deficit accrued as a result of the management of patients with TBI at an MTC. The more complex the presentation, extensive the intervention, and lengthy the stay, the greater the deficit accrued by the centre. The current tariff payment system is not effectively reflecting the severity of injury or intensity of management of patients with TBI.

Comparison of the use of ventricular access devices and ventriculosubgaleal shunts in posthaemorrhagic hydrocephalus: systematic review and meta-analysis.

INTRODUCTION: Ventricular access devices (VAD) and ventriculosubgaleal shunts (VSGS) are currently both used as temporising devices to affect CSF drainage in neonatal posthaemorrhagic hydrocephalus (PHH), without clear evidence of superiority of either procedure. In this systematic review and meta-analysis, we compared the VSGS and VAD regarding complication rates, ventriculoperitoneal shunt conversion and infection rates, and mortality and long-term disability. METHODS: The review was registered with the PROSPERO international prospective register of systematic reviews (registration number CRD42015019750) and was conducted in accordance with PRISMA guidelines. RESULTS AND CONCLUSIONS: The literature search of five databases identified 338 publications, of which 5 met the inclusion criteria. All were retrospective cohort studies (evidence class 3b and 4). A significantly lower proportion of patients with a VSGS required CSF tapping compared to patients with a VAD (log OR -4.43, 95% CI -6.14 to -2.72). No other significant differences between the VAD and VSGS were identified in their rates of infection (log OR 0.03, 95% CI -0.77 to 0.84), obstruction (log OR 1.25, 95% CI -0.21 to 2.71), ventriculoperitoneal shunt dependence (log OR -0.06, 95% CI -0.93 to 0.82), subsequent shunt infection (log OR 0.23, 95% CI -0.61 to 1.06), mortality (log OR 0.37, 95% CI -0.95 to 1.70) or long-term disability (p = 0.9). In all studies, there was a lack of standardised criteria, variations between surgeons in heterogeneous cohorts of limited sample size and a lack of neurodevelopmental follow-up. This affirms the importance of an ongoing multicentre, prospective pilot study comparing these two temporising procedures to enable a more robust comparison.

Anti-NMDA Encephalitis in the Acute Setting.

BACKGROUND: Encephalitis associated with antibodies targeted against the N-methyl-D-aspartate (NMDA) receptor is increasingly recognised as a major cause of an acute presentation of organic psychosis. Misdiagnosis and subsequent inappropriate referral to psychiatric services is common and avoidable. This review focuses on addressing this issue in the acute setting. METHODS: The authors present a review of existing literature relating to the pathophysiology and presentation of anti-NMDA receptor encephalitis, prior to proposing a management pathway avoiding delays to treatment incurred through misdiagnosis or inappropriate referral. CONCLUSIONS: Acute care physicians should have a low threshold for suspecting anti-NMDA receptor encephalitis in any patient presenting with acute psychosis in the context of non-specific coryzal and constitutional symptoms in whom infective causes have been excluded. The presence of pleocytosis and reduced protein in routine CSF analysis should further raise suspicion, and samples should be sent for immunohistochemical testing. Availability and efficiency of this testing is currently suboptimal.

The management of incidental meningioma: An unresolved clinical conundrum.

The widespread availability and use of brain magnetic resonance imaging and computed tomography has led to an increase in the frequency of incidental meningioma diagnoses. Most incidental meningioma are small, demonstrate indolent behavior during follow-up, and do not require intervention. Occasionally, meningioma growth causes neurological deficits or seizures prompting surgical or radiation treatment. They may cause anxiety to the patient and present a management dilemma for the clinician. The questions for both patient and clinician are "will the meningioma grow and cause symptoms such that it will require treatment within my lifetime?" and "will deferment of treatment result in greater treatment-related risks and lower chance of cure?." International consensus guidelines recommend regular imaging and clinical follow-up, but the duration is not specified. Upfront treatment with surgery or stereotactic radiosurgery/radiotherapy may be recommended but this is potentially an overtreatment, and its benefits must be balanced against the risk of related adverse events. Ideally, treatment should be stratified based on patient and tumor characteristics, but this is presently hindered by low-quality supporting evidence. This review discusses risk factors for meningioma growth, proposed management strategies, and ongoing research in the field.

Variation in postoperative outcomes of patients with intracranial tumors: insights from a prospective international cohort study during the COVID-19 pandemic.

BACKGROUND: This study assessed the international variation in surgical neuro-oncology practice and 30-day outcomes of patients who had surgery for an intracranial tumor during the COVID-19 pandemic. METHODS: We prospectively included adults aged ≥18 years who underwent surgery for a malignant or benign intracranial tumor across 55 international hospitals from 26 countries. Each participating hospital recorded cases for 3 consecutive months from the start of the pandemic. We categorized patients' location by World Bank income groups (high [HIC], upper-middle [UMIC], and low- and lower-middle [LLMIC]). Main outcomes were a change from routine management, SARS-CoV-2 infection, and 30-day mortality. We used a Bayesian multilevel logistic regression stratified by hospitals and adjusted for key confounders to estimate the association between income groups and mortality. RESULTS: Among 1016 patients, the number of patients in each income group was 765 (75.3%) in HIC, 142 (14.0%) in UMIC, and 109 (10.7%) in LLMIC. The management of 200 (19.8%) patients changed from usual care, most commonly delayed surgery. Within 30 days after surgery, 14 (1.4%) patients had a COVID-19 diagnosis and 39 (3.8%) patients died. In the multivariable model, LLMIC was associated with increased mortality (odds ratio 2.83, 95% credible interval 1.37-5.74) compared to HIC. CONCLUSIONS: The first wave of the pandemic had a significant impact on surgical decision-making. While the incidence of SARS-CoV-2 infection within 30 days after surgery was low, there was a disparity in mortality between countries and this warrants further examination to identify any modifiable factors.

External validation and recalibration of an incidental meningioma prognostic model - IMPACT: protocol for an international multicentre retrospective cohort study.

INTRODUCTION: Due to the increased use of CT and MRI, the prevalence of incidental findings on brain scans is increasing. Meningioma, the most common primary brain tumour, is a frequently encountered incidental finding, with an estimated prevalence of 3/1000. The management of incidental meningioma varies widely with active clinical-radiological monitoring being the most accepted method by clinicians. Duration of monitoring and time intervals for assessment, however, are not well defined. To this end, we have recently developed a statistical model of progression risk based on single-centre retrospective data. The model Incidental Meningioma: Prognostic Analysis Using Patient Comorbidity and MRI Tests (IMPACT) employs baseline clinical and imaging features to categorise the patient with an incidental meningioma into one of three risk groups: low, medium and high risk with a proposed active monitoring strategy based on the risk and temporal trajectory of progression, accounting for actuarial life expectancy. The primary aim of this study is to assess the external validity of this model. METHODS AND ANALYSIS: IMPACT is a retrospective multicentre study which will aim to include 1500 patients with an incidental intracranial meningioma, powered to detect a 10% progression risk. Adult patients ≥16 years diagnosed with an incidental meningioma between 1 January 2009 and 31 December 2010 will be included. Clinical and radiological data will be collected longitudinally until the patient reaches one of the study endpoints: intervention (surgery, stereotactic radiosurgery or fractionated radiotherapy), mortality or last date of follow-up. Data will be uploaded to an online Research Electronic Data Capture database with no unique identifiers. External validity of IMPACT will be tested using established statistical methods. ETHICS AND DISSEMINATION: Local institutional approval at each participating centre will be required. Results of the study will be reported through peer-reviewed articles and conferences and disseminated to participating centres, patients and the public using social media.