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Vestibular schwannomas are benign nerve sheath tumours that arise on the vestibulocochlear nerves. Vestibular schwannomas are known to occur in the context of tumour predisposition syndromes NF2-related and LZTR1-related schwannomatosis. However, the majority of vestibular schwannomas present sporadically without identification of germline pathogenic variants.To identify novel genetic associations with risk of vestibular schwannoma development, we conducted a genome-wide association study in a cohort of 911 sporadic vestibular schwannoma cases collated from the neurofibromatosis type 2 genetic testing service in the north-west of England, UK and 5500 control samples from the UK Biobank resource. One risk locus reached genome-wide significance in our association analysis (9p21.3, rs1556516, P = 1.47 × 10−13, odds ratio = 0.67, allele frequency = 0.52).9p21.3 is a genome-wide association study association hotspot, and a number of genes are localized to this region, notably CDKN2B-AS1 and CDKN2A/B, also referred to as the INK4 locus. Dysregulation of gene products within the INK4 locus have been associated with multiple pathologies and the genes in this region have been observed to directly impact the expression of one another. Recurrent associations of the INK4 locus with components of well-described oncogenic pathways provides compelling evidence that the 9p21.3 region is truly associated with risk of vestibular schwannoma tumorigenesis.

Purpose There is no compelling outcome data or clear guidance surrounding postoperative venous thromboembolism (VTE) prophylaxis using low molecular weight heparin (chemoprophylaxis) in patients undergoing pituitary surgery. Here we describe our experience of early chemoprophylaxis (post-operative day 1) following trans-sphenoidal pituitary surgery. Methods Single-centre review of a prospective surgical database and VTE records. Adults undergoing first time trans-sphenoidal pituitary surgery were included (2009–2018). VTE was defined as either deep vein thrombosis and/or pulmonary embolism within 3 months of surgery. Postoperative haematomas were those associated with a clinical deterioration together with radiological evidence. Results 651 Patients included with a median age of 55 years (range 16–86 years). Most (99%) patients underwent trans-sphenoidal surgery using a standard endoscopic single nostril or bi-nostril trans-sphenoidal technique. More than three quarters had pituitary adenomas (n = 520, 80%). Postoperative chemoprophylaxis to prevent VTE was administered in 478 patients (73%). Chemoprophylaxis was initiated at a median of 1 day post-procedure (range 1–5 days postoperatively; 92% on postoperative day 1). Tinzaparin was used in 465/478 patients (97%) and enoxaparin was used in 14/478 (3%). There were no cases of VTE, even in 78 ACTH-dependent Cushing’s disease patients. Six patients (1%) developed postoperative haematomas. Chemoprophylaxis was not associated with a significantly higher rate of postoperative haematoma formation (Fisher’s Exact, p = 0.99) or epistaxis (Fisher’s Exact, p > 0.99). Conclusions Chemoprophylaxis after trans-sphenoidal pituitary surgery on post-operative day 1 is a safe strategy to reduce the risk of VTE without significantly increasing the risk of postoperative bleeding events.

PURPOSE: To assess and compare outcome of surgical management of non-functioning pituitary adenohypophyseal tumours in patients under 65-years, and 65-years and older at tertiary neurosurgical referral centre.METHODS: Data was retrospectively analysed from pituitary database. Forty-four patients aged 65 or older (Group 1) and 93 patients under 65 (Group 2) underwent endoscopic trans-sphenoidal surgery (ETSS) between January 2017 and July 2019. The surgical, endocrinological, ophthalmological and radiological outcomes were compared.RESULTS: 6.8% of Group 1 patients had peri-operative surgical complications compared to 12.9% in Group 2 (p = 0.29). Improved visual fields and acuity were seen in 65.2% and 82.8% of Group 1 and Group 2 respectively (p = 0.124), although there were pre-existing ocular problems in 15.9% of Group 1. New hormone deficiencies were observed in 31.8% of Group 1 patients, and 24.7% of Group 2 (p = 0.555). Tumour regrowth/recurrence was seen in 2.3% of Group 1 (p = 0.553). The rate of repeat surgery was 6.8% in the Group 1 and 12.9% in Group 2 (p = 0.28). There was no significant relationship between extent of resection, complications or hormonal deficiency. The mean duration of follow-up was 10.5 ± 13.0 months for Group 1 patients and 13.0 ± 16.0 months for Group 2 patients (p = 0.526).CONCLUSIONS: ETSS for non-functioning pituitary adenohypophyseal tumours is safe and well tolerated in the patients aged 65 and older. Advanced age by itself should not be a contra-indication for ETSS. It is however highly recommended that the care of such patients to be offered at a high volume, dedicated pituitary surgical units.

Objective The study aimed to determine long-term outcomes in patients with intraoperative electrical conduction block in an anatomically intact facial nerve (FN). Methods Single center retrospective review of prospectively collected database of all vestibular schwannoma surgeries between January 1, 2008 and August 25, 2015. Operative notes were reviewed and patients with anatomically intact FNs, but complete conduction block at the end of surgery were included for analysis. Results In total, 371 patients had vestibular schwannoma surgery of which 18 met inclusion criteria. Mean follow-up was 34.28 months and average tumor size was 28.00 mm. Seventeen patients had House-Brackmann Grade VI facial palsy immediately postoperatively and one patient was grade V. At 1 year, three patients remained grade VI (17%), two improved to grade V (11%), seven to grade IV (39%), six to grade III (33%), and one patient to grade II (6%). On extended follow-up, five patients (28%) had additional 1 to 2 score improvement in facial function. Subset analysis revealed no correlation of tumor size, vascularity, adherence to nerve, operative approach, extent of resection, splaying of FN, and recurrent tumor or sporadic tumors to the extent of FN recovery. Conclusion Intraoperative conduction block does not condemn a patient to permanent FN palsy. There is potential for a degree of recovery comparable with those undergoing nerve grafting. Our data do not clearly support a policy of same-surgery or early-postoperative primary nerve grafting in the event of a complete conduction block, and instead we favor monitoring for recovery in an anatomically intact nerve.

Meningiomas are the most common primary brain tumor and their incidence and prevalence is increasing. This review summarizes current evidence regarding the embryogenesis of the human meninges in the context of meningioma pathogenesis and anatomical distribution. Though not mutually exclusive, chromosomal instability and pathogenic variants affecting the long arm of chromosome 22 (22q) result in meningiomas in neural-crest cell-derived meninges, while variants affecting Hedgehog signaling, PI3K signaling,TRAF7,KLF4, andPOLR2Aresult in meningiomas in the mesodermal-derived meninges of the midline and paramedian anterior, central, and ventral posterior skull base. Current evidence regarding the common pathways for genetic pathogenesis and the anatomical distribution of meningiomas is presented alongside existing understanding of the embryological origins for the meninges prior to proposing next steps for this work.

Primary non-neuroendocrine tumours of the pituitary gland and sella are rare lesions often challenging to diagnose. We describe two cases of clinically aggressive primary glomus tumour of the pituitary gland. The lesions occurred in a 63-year-old male and a 30-year-old female who presented with headache, blurred vision and hypopituitarism. Neuroimaging demonstrated large sellar and suprasellar tumours invading the surrounding structures. Histologically, the lesions were characterised by angiocentric sheets and nests of atypical cells that expressed vimentin, smooth muscle actin and CD34. Perivascular deposition of collagen IV was also a feature. Case 2 expressed synaptophysin. INI-1 (SMARCB1) expression was preserved. Both lesions were mitotically active and demonstrated a Ki-67 labelling index of 30%. Next-generation sequencing performed in case 1 showed no mutations in the reading frame of 37 commonly mutated oncogenes, including BRAF and KRAS. Four pituitary glomus tumours have previously been reported, none of which showed features of malignant glomus tumour. Similar to our two patients, three previous examples displayed aggressive behaviour.

Introduction Vestibular schwannomas (VS) are histologically benign tumors arising from cranial nerve VIII. Far from a homogenous proliferation of Schwann cells, mounting evidence has highlighted the complex nature of the inflammatory microenvironment in these tumors. Methods A review of the literature pertaining to inflammation, inflammatory molecular pathways, and immune-related therapeutic targets in VS was performed. Relevant studies published up to June 2020 were identified based on a literature search in the PubMed and MEDLINE databases and the findings were synthesized into a concise narrative review of the topic. Results The VS microenvironment is characterized by a dense infiltrate of inflammatory cells, particularly macrophages. Significantly higher levels of immune cell infiltration are observed in growing versus static tumors, and there is a demonstrable interplay between inflammation and angiogenesis in growing VS. While further mechanistic studies are required to ascertain the exact role of inflammation in angiogenesis, tumor growth, and Schwann cell control, we are beginning to understand the key molecular pathways driving this inflammatory microenvironment, and how these processes can be monitored and targeted in vivo. Conclusion Observational research has revealed a complex and heterogeneous tumor microenvironment in VS. The functional landscape and roles of macrophages and other immune cells in the VS inflammatory infiltrate are, however, yet to be established. The antiangiogenic drug bevacizumab has shown the efficacy of targeted molecular therapies in VS and there is hope that agents targeting another major component of the VS microenvironment, inflammation, will also find a place in their future management.

PURPOSE: To evaluate the incidence of mosaicism in de novo neurofibromatosis 2 (NF2).METHODS: Patients fulfilling NF2 criteria, but with no known affected family member from a previous generation (n = 1055), were tested for NF2 variants in lymphocyte DNA and where available tumor DNA. The proportion of individuals with a proven or presumed mosaic NF2 variant was assessed and allele frequencies of identified variants evaluated using next-generation sequencing.RESULTS: The rate of proven/presumed mosaicism was 232/1055 (22.0%). However, nonmosaic heterozygous pathogenic variants were only identified in 387/1055 (36.7%). When variant detection rates in second generation nonmosaics were applied to de novo cases, we assessed the overall probable mosaicism rate to be 59.7%. This rate differed by age from 21.7% in those presenting with bilateral vestibular schwannoma CONCLUSION: This study has identified a very high probable mosaicism rate in de novo NF2, probably making NF2 the condition with the highest expressed rate of mosaicism in de novo dominant disease that is nonlethal in heterozygote form. Risks to offspring are small and probably correlate with variant allele frequency detected in blood.

Aim: To develop a nonviral tool for the delivery of siRNA to brain tumor cells using peptide nanofibers (PNFs). Materials & methods: Uptake of PNFs was evaluated by confocal microscopy and flow cytometry. Gene silencing was determined by RT-qPCR and cell invasion assay. Results: PNFs enter phagocytic (BV-2) and nonphagocytic (U-87 MG) cells via endocytosis and passive translocation. si PLK1 delivered using PNFs reduced the expression of polo-like kinase 1 mRNA and induced cell death in a panel of immortalized and glioblastoma-derived stem cells. Moreover, targeting MMP2 using PNF:si MMP2 reduced the invasion capacity of U-87 MG cells. We show that stereotactic intra-tumoral administration of PNF:si PLK1 significantly extends the survival of tumor bearing mice comparing with the untreated tumor bearing animals. Conclusion: Our results suggest that this nanomedicine-based RNA interference approach deserves further investigation as a potential brain tumor therapeutic tool.

Simple Summary Primary skull base chondrosarcomas (SBCs) may carry significant tumor-burden by causing severe cranial nerve neuropathies. Current treatment strategies mainly focus on surgical resection and radiotherapy protocols, with a wide range of findings in terms of efficacy and safety. The aim of our systematic review was to comprehensively analyze the current literature on primary SBCs, describing clinical and radiological characteristics, available management strategies, treatment outcomes, and prognoses. We found that most primary SBCs show benign slow-growing patterns but may cause neurological deficits by compressing critical neurovascular structures. Open surgical approaches favor maximal resection with acceptable complication rates, but only a few studies reported the use of newer endoscopic approaches. Proton-based, photon-based, and carbon-based radiotherapy protocols may also allow safe and effective local tumor control as adjuvant treatments or stand-alone strategies in patients not eligible to undergo surgery. Overall, primary SBCs’ prognoses proved to be favorable and comparable to benign skull base neoplasms. Abstract Background: Primary skull base chondrosarcomas (SBCs) can severely affect patients’ quality of life. Surgical-resection and radiotherapy are feasible but may cause debilitating complications. We systematically reviewed the literature on primary SBCs. Methods: PubMed, EMBASE, Scopus, Web-of-Science, and Cochrane were searched following the PRISMA guidelines to include studies of patients with primary SBCs. Clinical characteristics, management strategies, and treatment outcomes were analyzed. Results: We included 33 studies comprising 1307 patients. Primary SBCs mostly involved the middle-fossa (72.7%), infiltrating the cavernous-sinus in 42.4% of patients. Cranial-neuropathies were reported in 810 patients (62%). Surgical-resection (93.3%) was preferred over biopsy (6.6%). The most frequent open surgical approaches were frontotemporal-orbitozygomatic (17.6%) and pterional (11.9%), and 111 patients (21.3%) underwent endoscopic-endonasal resection. Post-surgical cerebrospinal-fluid leaks occurred in 36 patients (6.5%). Radiotherapy was delivered in 1018 patients (77.9%): photon-based (41.4%), proton-based (64.2%), and carbon-based (13.1%). Severe post-radiotherapy complications, mostly hypopituitarism (15.4%) and hearing loss (7.1%) were experienced by 251 patients (30.7%). Post-treatment symptom-improvement (46.7%) and reduced/stable tumor volumes (85.4%) showed no differences based on radiotherapy-protocols (p = 0.165; p = 0.062). Median follow-up was 67-months (range, 0.1–376). SBCs recurrences were reported in 211 cases (16.1%). The 5-year and 10-year progression-free survival rates were 84.3% and 67.4%, and overall survival rates were 94% and 84%. Conclusion: Surgical-resection and radiotherapy are effective treatments in primary SBCs, with acceptable complication rates and favorable local tumor control.

Purpose: A DCE-MRI technique that can provide both high spatiotemporal resolution and whole-brain coverage for quantitative microvascular analysis is highly desirable but currently challenging to achieve. In this study, we sought to develop and validate a novel dual-temporal resolution (DTR) DCE-MRI-based methodology for deriving accurate, whole-brain high-spatial resolution microvascular parameters. Methods: Dual injection DTR DCE-MRI was performed and composite high-temporal and high-spatial resolution tissue gadolinium-based-contrast agent (GBCA) concentration curves were constructed. The high-temporal but low-spatial resolution first-pass GBCA concentration curves were then reconstructed pixel-by-pixel to higher spatial resolution using a process we call LEGATOS. The accuracy of kinetic parameters (K trans, v p, and v e) derived using LEGATOS was evaluated through simulations and in vivo studies in 17 patients with vestibular schwannoma (VS) and 13 patients with glioblastoma (GBM). Tissue from 15 tumors (VS) was examined with markers for microvessels (CD31) and cell density (hematoxylin and eosin [H&E]). Results: LEGATOS derived parameter maps offered superior spatial resolution and improved parameter accuracy compared to the use of high-temporal resolution data alone, provided superior discrimination of plasma volume and vascular leakage effects compared to other high-spatial resolution approaches, and correlated with tissue markers of vascularity (P ≤ 0.003) and cell density (P ≤ 0.006). Conclusion: The LEGATOS method can be used to generate accurate, high-spatial resolution microvascular parameter estimates from DCE-MRI.

Stereotactic radiosurgery (SRS) is an established, effective therapy against vestibular schwannoma (VS). The mechanisms of tumour response are, however, unknown and in this study we sought to evaluate changes in the irradiated VS tumour microenvironment through a multinuclear MRI approach. Five patients with growing sporadic VS underwent a multi-timepoint comprehensive MRI protocol, which included diffusion tensor imaging (DTI), dynamic contrast-enhanced (DCE) MRI and a spiral 23Na-MRI acquisition for total sodium concentration (TSC) quantification. Post-treatment voxelwise changes in TSC, DTI metrics and DCE-MRI derived microvascular biomarkers (Ktrans, ve and vp) were evaluated and compared against pre-treatment values. Changes in tumour TSC and microvascular parameters were observable as early as 2 weeks post-treatment, preceding changes in structural imaging. At 6 months post-treatment there were significant voxelwise increases in tumour TSC (p p p

Purpose: We have evaluated deficiencies in existing diagnostic criteria for neurofibromatosis 2 (NF2). Methods: Two large databases of individuals fulfilling NF2 criteria (n=1361) and those tested for NF2 variants with criteria short of diagnosis (n=1416) were interrogated. We assessed the proportions meeting each diagnostic criterion with constitutional or mosaic NF2 variants and the Positive Predictive Value (PPV) with regard to definite diagnosis.Results: There was no evidence for usefulness of old criteria ‘glioma’ or ‘neurofibroma’. ‘Ependymoma’ had 100% PPV and high levels of confirmed NF2 diagnosis (67.7%). Those with bilateral vestibular schwannoma (VS) alone aged ≥60 years had the lowest confirmation rate (6.6%) and reduced PPV(80%). Siblings as a first-degree-relative, without an affected parent, had 0% PPV. All three individuals with unilateral VS and an affected sibling were proven not to have NF2. The biggest overlap was with LZTR1-associated schwannomatosis. In this category, seven individuals with unilateral VS plus ≥2 non-dermal schwannomas reduced PPV to 67%.Conclusion: The present study has confirmed important deficiencies in NF2 diagnostic criteria. The term ‘glioma’ should be dropped and replaced by ‘ependymoma’. Similarly ‘neurofibroma’ should be removed. Dropping ‘sibling’ from first-degree-relatives should be considered and testing of LZTR1 should be recommended for unilateral VS.

Objective: Although orbital surgery has always represented a challenge for neurosurgeons, keyhole and endoscopic techniques are gradually surging in popularity maximizing functional and esthetic outcomes. This quantitative anatomical study first compared the surgical operability achieved through three endoscopic approaches within the inferior orbit: the endoscopic sublabial transmaxillary (ESTMax), the endoscopic endonasal transethmoidal (EETEth), and the endoscope-assisted lateral orbitotomy (ELO). Methods: Each of these approaches was performed bilaterally on five specimens. We described the ESTMax step-by-step, underlining its advantages and pitfalls in comparison with EETEth and ELO. Then, we assessed surgical measurements and operability in ESTMax, EETEth, and ELO. Results: The ESTMax provided the most favorable operative window (278.9 ± 43.8 mm2; EETEth: 240.8 ± 21.5 mm2, p < 0.001; ELO: 263.1 ± 19.8 mm2, p = 0.006), the broadest surgical field area (415.9 ± 26.4 mm2; EETEth: 386.7 ± 30.1 mm2, p = 0.041; ELO: 305.2 ± 26.3 mm2, p < 0.001), surgical field depths significantly shorter than EETEth (p < 0.001) but similar to ELO, the widest surgical angles of attack (45°–65°; EETEth: 20°–30°, p < 0.001; ELO: 25°–50°, p < 0.001), and the greatest surgical mobility areas (EETEth: p < 0.001; ELO: p < 0.001). Furthermore, the ESTMax allowed multi-angled exposure and handy maneuverability around all the inferior intraorbital targets. Small anterior antrostomy, blunt intraorbital dissections, direct targets’ approach, orbital floor reconstruction, and maxillary bone flap replacement may limit the ESTMax morbidity rates. Conclusions: The ESTMax is a minimally invasive “head-on” orbital approach that exploits endoscopic surgery advantages avoiding the cranio-orbital and trans-nasal approach limitations and possible complications. It represents a promising alternative to EETEth and ELO because of its optimal operability for resecting lesions extending into the entire inferior orbit.

Background CRANIAL (CSF Rhinorrhoea After Endonasal Intervention to the Skull Base) is a prospective multicenter observational study seeking to determine 1) the scope of skull base repair methods used and 2) corresponding rates of postoperative cerebrospinal fluid (CSF) rhinorrhea in the endonasal transsphenoidal approach (TSA) and the expanded endonasal approach (EEA) for skull base tumors. We sought to pilot the project, assessing the feasibility and acceptability by gathering preliminary data. Methods A prospective observational cohort study was piloted at 12 tertiary neurosurgical units in the United Kingdom. Feedback regarding project positives and challenges were qualitatively analyzed. Results A total of 187 cases were included: 159 TSA (85%) and 28 EEA (15%). The most common diseases included pituitary adenomas (n = 142/187), craniopharyngiomas (n = 13/187). and skull base meningiomas (n = 4/187). The most common skull base repair techniques used were tissue glues (n = 132/187, most commonly Tisseel), grafts (n = 94/187, most commonly fat autograft or Spongostan) and vascularized flaps (n = 51/187, most commonly nasoseptal). These repairs were most frequently supported by nasal packs (n = 125/187) and lumbar drains (n = 20/187). Biochemically confirmed CSF rhinorrhea occurred in 6/159 patients undergoing TSA (3.8%) and 2/28 patients undergoing EEA (7.1%). Four patients undergoing TSA (2.5%) and 2 patients undergoing EEA (7.1%) required operative management for CSF rhinorrhea (CSF diversion or direct repair). Qualitative feedback was largely positive (themes included user-friendly and efficient data collection and strong support from senior team members), demonstrating acceptability. Conclusions Our pilot experience highlights the acceptability and feasibility of CRANIAL. There is a precedent for multicenter dissemination of this project, to establish a benchmark of contemporary practice in skull base neurosurgery, particularly with respect to patients undergoing EEA.

Background Limited data exist on the disease course of neurofibromatosis type 2 (NF2) to guide clinical trial design. Methods A prospective database of patients meeting NF2 diagnostic criteria, reviewed between 1990 and 2020, was evaluated. Follow-up to first vestibular schwannoma (VS) intervention and death was assessed by univariate analysis and stratified by age at onset, era referred, and inheritance type. Interventions for NF2-related tumors were assessed. Cox regression was performed to determine the relationship between individual factors from time of diagnosis to NF2-related death. Results Three hundred and fifty-three patients were evaluated. During 4643.1 follow-up years from diagnosis to censoring, 60 patients (17.0%) died. The annual mean number of patients undergoing VS surgery or radiotherapy declined, from 4.66 and 1.65, respectively, per 100 NF2 patients in 1990-1999 to 2.11 and 1.01 in 2010-2020, as the number receiving bevacizumab increased (2.51 per 100 NF2 patients in 2010-2020). Five patients stopped bevacizumab to remove growing meningioma or spinal schwannoma. 153/353 (43.3%) had at least one neurosurgical intervention/radiation treatment within 5 years of diagnosis. Patients asymptomatic at diagnosis had longer time to intervention and better survival compared to those presenting with symptoms. Those symptomatically presenting 40 years had poorer overall survival than those presenting at 26-39 years (P = .03 and P = .02, respectively) but those presenting between 16 and 39 had shorter time to VS intervention. Individuals with de novo constitutional variants had worse survival than those with de novo mosaic or inherited disease (P = .004). Conclusion Understanding disease course improves prognostication, allowing for better-informed decisions about care.

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.

ObjectivesCases of sporadic vestibular schwannoma (sVS) have a low rate of association with germline pathogenic variants. However, some individuals with sVS can represent undetected cases of neurofibromatosis type 2 (NF2) or schwannomatosis. Earlier identification of patients with these syndromes can facilitate more accurate familial risk prediction and prognosis.MethodsCases of sVS were ascertained from a local register at the Manchester Centre for Genomic Medicine. Genetic analysis was conducted in NF2 on blood samples for all patients, and tumour DNA samples when available. LZTR1 and SMARCB1 screening was also performed in patient subgroups.ResultsAge at genetic testing for vestibular schwannoma (VS) presentation was younger in comparison with previous literature, a bias resulting from updated genetic testing recommendations. Mosaic or constitutional germline NF2 variants were confirmed in 2% of patients. Pathogenic germline variants in LZTR1 were found in 3% of all tested patients, with a higher rate of 5% in patients SMARCB1 variants were identified within the cohort. Considering all individuals who received tumour DNA analysis, 69% of patients were found to possess two somatic pathogenic NF2 variants, including those with germline LZTR1 pathogenic variants.ConclusionsUndiagnosed schwannoma predisposition may account for a significant minority of apparently sVS cases, especially at lower presentation ages. Loss of NF2 function is a common event in VS tumours and may represent a targetable common pathway in VS tumourigenesis. These data also support the multi-hit mechanism of LZTR1-associated VS tumourigenesis.

Vestibular schwannomas are tumors arising from the vestibulocochlear nerve at the cerebellopontine angle. Their proximity to eloquent brainstem structures means that the pathology itself and the treatment thereof can be associated with significant morbidity. The vast majority of these tumors are sporadic, with the remainder arising as a result of the genetic syndrome Neurofibromatosis Type 2 or, more rarely, LZTR1-related schwannomatosis. The natural history of these tumors is extremely variable, with some tumors not displaying any evidence of growth, others demonstrating early, persistent growth and a small number growing following an extended period of indolence. Emerging evidence now suggests that far from representing Schwann cell proliferation only, the tumor microenvironment is complex, with inflammation proposed to play a key role in their growth. In this review, we provide an overview of this new evidence, including the role played by immune cell infiltration, the underlying molecular pathways involved, and biomarkers for detecting this inflammation in vivo. Given the limitations of current treatments, there is a pressing need for novel therapies to aid in the management of this condition, and we conclude by proposing areas for future research that could lead to the development of therapies targeted toward inflammation in vestibular schwannoma.

Objectives/hypothesis Unilateral vestibular schwannoma (VS) occurs with a lifetime risk of around 1 in 1,000 and is due to inactivation of the NF2 gene, either somatically or from a constitutional mutation. It has been postulated that familial occurrence of unilateral VS occurs more frequently than by chance, but no causal mechanism has been confirmed. Study design Retrospective database analysis. Methods The likelihood of chance occurrence of unilateral VS, or occurring in the context of neurofibromatosis type 2 (NF2), was assessed using national UK audit data and data from the national NF2 database. Families with familial unilateral VS (occurrence in first- and second-degree relatives) were assessed for constitutional NF2 and LZTR1 genetic variants, and where possible the tumor was also analyzed. Results Approximately 1,000 cases of unilateral VS occurred annually in the United Kingdom between 2013 and 2016. Of these, 2.5 may be expected to have a first-degree relative who had previously developed a unilateral VS. The likelihood of this occurring in NF2 was considered to be as low as 0.05 annually. None of 28 families with familial unilateral VS had a constitutional NF2 intragenic variant, and in nine cases where the VS was analyzed, both mutational events in NF2 were identified and excluded from the germline. Only three variants of uncertain significance were found in LZTR1. Conclusions Familial occurrence of unilateral VS is very unlikely to be due to a constitutional NF2 or definitely pathogenic LZTR1 variant. The occurrence of unilateral VS in two or more first-degree relatives is likely due to chance. This phenomenon may well increase in clinical practice with increasing use of cranial magnetic resonance imaging in older patients. Level of evidence 2b Laryngoscope, 129:967-973, 2019.

OBJECTIVE Inflammation and angiogenesis may play a role in the growth of sporadic and neurofibromatosis type 2 (NF2)–related vestibular schwannoma (VS). The similarities in microvascular and inflammatory microenvironment have not been investigated. The authors sought to compare the tumor microenvironment (TME) in sporadic and NF2-related VSs using a combined imaging and tissue analysis approach. METHODS Diffusion MRI and high-temporal-resolution dynamic contrast-enhanced (DCE) MRI data sets were prospectively acquired in 20 NF2-related and 24 size-matched sporadic VSs. Diffusion metrics (mean diffusivity, fractional anisotropy) and DCE-MRI–derived microvascular biomarkers (transfer constant [Ktrans], fractional plasma volume, tissue extravascular-extracellular space [ve], longitudinal relaxation rate, tumoral blood flow) were compared across both VS groups, and regression analysis was used to evaluate the effect of tumor size, pretreatment tumor growth rate, and tumor NF2 status (sporadic vs NF2-related) on each imaging parameter. Tissues from 17 imaged sporadic VSs and a separate cohort of 12 NF2-related VSs were examined with immunohistochemistry markers for vessels (CD31), vessel permeability (fibrinogen), and macrophage density (Iba1). The expression of vascular endothelial growth factor (VEGF) and VEGF receptor 1 was evaluated using immunohistochemistry, Western blotting, and double immunofluorescence. RESULTS Imaging data demonstrated that DCE-MRI–derived microvascular characteristics were similar in sporadic and NF2-related VSs. Ktrans (p < 0.001), ve (p ≤ 0.004), and tumoral free water content (p ≤ 0.003) increased with increasing tumor size and pretreatment tumor growth rate. Regression analysis demonstrated that with the exception of mean diffusivity (p < 0.001), NF2 status had no statistically significant effect on any of the imaging parameters or the observed relationship between the imaging parameters and tumor size (p > 0.05). Tissue analysis confirmed the imaging metrics among resected sporadic VSs and demonstrated that across all VSs studied, there was a close association between vascularity and Iba1+ macrophage density (r = 0.55, p = 0.002). VEGF was expressed by Iba1+ macrophages. CONCLUSIONS The authors present the first in vivo comparative study of microvascular and inflammatory characteristics in sporadic and NF2-related VSs. The imaging and tissue analysis results indicate that inflammation is a key contributor to TME and should be viewed as a therapeutic target in both VS groups.

ObjectivesSchwannomatosis is a dominantly inherited condition predisposing to schwannomas of mainly spinal and peripheral nerves with some diagnostic overlap with neurofibromatosis-2 (NF2), but the underlying epidemiology is poorly understood. We present the birth incidence and prevalence allowing for overlap with NF2.MethodsSchwannomatosis and NF2 cases were ascertained from the Manchester region of England (population=4.8 million) and from across the UK. Point prevalence and birth incidence were calculated from regional birth statistics. Genetic analysis was also performed on NF2, LZTR1 and SMARCB1 on blood and tumour DNA samples when available.ResultsRegional prevalence for schwannomatosis and NF2 were 1 in 126 315 and 50 500, respectively, with calculated birth incidences of 1 in 68 956 and 1 in 27 956. Mosaic NF2 causes a substantial overlap with schwannomatosis resulting in the misdiagnosis of at least 9% of schwannomatosis cases. LZTR1-associated schwannomatosis also causes a small number of cases that are misdiagnosed with NF2 (1%–2%), due to the occurrence of a unilateral vestibular schwannoma. Patients with schwannomatosis had lower numbers of non-vestibular cranial schwannomas, but more peripheral and spinal nerve schwannomas with pain as a predominant presenting symptom. Life expectancy was significantly better in schwannomatosis (mean age at death 76.9) compared with NF2 (mean age at death 66.2; p=0.004).ConclusionsWithin the highly ascertained North-West England population, schwannomatosis has less than half the birth incidence and prevalence of NF2.

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

Introduction: Silent corticotroph adenomas (SCA) represent 3-6% of all pituitary adenomas. SCA are confirmed on post-surgical histological tumour staining and can either have no prior clinical or biochemical evidence of excess ACTH or alternatively only biochemical (not clinical) evidence of Cushing’s disease. SCA are potentially large and aggressive tumours with a greater tendency to post-surgical recurrence. We present a case of a giant SCA which pre-operatively didn’t exhibit any clinical signs of cortisol excess but showed signs of early recurrence on follow up imaging. Case: A 40-year-old man presented with frontal and maxillary sinus pain and nasal stuffiness. Nasal endoscopy revealed a mass in the nasal cavity and sphenoid sinus. Subsequent CT scan of his sinuses and MRI Pituitary reported a 4 x 3.5 x 2.5 cm sellar mass extending through the floor of sella into the sphenoid sinus and nasal cavity. Despite no clinical features of any pituitary hormone excess (including Cushing’s) or deficiency, his biochemical parameters were consistent with hypercortisolaemia. Post-low dose dexamethasone (2 mg over 48 hours) suppression cortisol was inadequate: 106 nmol/L (3nmol/L), ACTH 46 ng/L (0-46 ng/L) and 24-hour urinary free cortisol levels were 502 and 260 nmol/24 hours ( Conclusion: Our patient solely had biochemical (not clinical) evidence of Cushing’s disease despite a large pituitary tumour in keeping with an SCA, which are aggressive, have high recurrence rate and shorter time to recurrence after surgery. Close and frequent post-operative clinical, biochemical and radiological surveillance is critical to detect and manage early recurrence that may require multimodal therapy.

The authors present the case of a 24-year-old female with neurofibromatosis type 2. Growth of the left vestibular schwannoma and progressive hearing loss prompted the decision to proceed to translabyrinthine resection with cochlear nerve preservation and cochlear implant insertion. Complete resection with preservation of the facial and cochlear nerves was achieved. The patient had grade 1 facial function and was discharged on postoperative day 4 following suturing of a minor CSF leak. This case highlights the feasibility of cochlear nerve preservation and cochlear implant insertion in appropriately selected patients, offering a combination of effective tumor control and hearing rehabilitation. The video can be found here: https://stream.cadmore.media/r10.3171/2021.7.FOCVID21122

To evaluate the incidence of mosaicism in de novo neurofibromatosis 2 (NF2).Patients fulfilling NF2 criteria, but with no known affected family member from a previous generation (n = 1055), were tested for NF2 variants in lymphocyte DNA and where available tumor DNA. The proportion of individuals with a proven or presumed mosaic NF2 variant was assessed and allele frequencies of identified variants evaluated using next-generation sequencing.The rate of proven/presumed mosaicism was 232/1055 (22.0%). However, nonmosaic heterozygous pathogenic variants were only identified in 387/1055 (36.7%). When variant detection rates in second generation nonmosaics were applied to de novo cases, we assessed the overall probable mosaicism rate to be 59.7%. This rate differed by age from 21.7% in those presenting with bilateral vestibular schwannoma20 years to 80.7% in those aged ≥60 years. A mosaic variant was detected in all parents of affected children with a single-nucleotide pathogenic NF2 variant.This study has identified a very high probable mosaicism rate in de novo NF2, probably making NF2 the condition with the highest expressed rate of mosaicism in de novo dominant disease that is nonlethal in heterozygote form. Risks to offspring are small and probably correlate with variant allele frequency detected in blood.

This case describes the strong utility of optical coherence tomography in multidisciplinary management of a complex case of type 2 neurofibromatosis.

ObjectivesBeing able to predict which patients with COVID-19 are going to deteriorate is important to help identify patients for clinical and research practice. Clinical prediction models play a critical role in this process, but current models are of limited value because they are typically restricted to baseline predictors and do not always use contemporary statistical methods. We sought to explore the benefits of incorporating dynamic changes in routinely measured biomarkers, non-linear effects and applying ‘state-of-the-art’ statistical methods in the development of a prognostic model to predict death in hospitalised patients with COVID-19.DesignThe data were analysed from admissions with COVID-19 to three hospital sites. Exploratory data analysis included a graphical approach to partial correlations. Dynamic biomarkers were considered up to 5 days following admission rather than depending solely on baseline or single time-point data. Marked departures from linear effects of covariates were identified by employing smoothing splines within a generalised additive modelling framework.Setting3 secondary and tertiary level centres in Greater Manchester, the UK.Participants392 hospitalised patients with a diagnosis of COVID-19.Results392 patients with a COVID-19 diagnosis were identified. Area under the receiver operating characteristic curve increased from 0.73 using admission data alone to 0.75 when also considering results of baseline blood samples and to 0.83 when considering dynamic values of routinely collected markers. There was clear non-linearity in the association of age with patient outcome.ConclusionsThis study shows that clinical prediction models to predict death in hospitalised patients with COVID-19 can be improved by taking into account both non-linear effects in covariates such as age and dynamic changes in values of biomarkers.

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

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

BackgroundThe Manchester criteria for Neurofibromatosis Type 2 (NF2) includes a range of tumours, and gliomas were incorporated in the original description. The gliomas are now widely accepted to be predominantly spinal cord ependymomas.ObjectWe have reviewed our database to determine whether these gliomas includes any cases of malignant glioma (WHO grade III and IV).MethodsThe prospective database consists of 1253 patients with NF2. 1009 are known to be alive at last follow up. ResultsThere was a single case of glioblastoma multiforme (GBM; WHO grade IV) in the series and no WHO grade III gliomas The GBM was in a patient who had previously undergone stereotactic radiosurgery for a vestibular schwannoma. ConclusionsHigh grade gliomas are not a feature of NF2 in the unirradiated patient and should be excluded from the diagnostic criteria.

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

Background The published literature suggests that malignant peripheral nerve sheath tumors (MPNST) occur at increased frequency in neurofibromatosis type 2 (NF2). A recent review based on incidence data in North America showed that 1 per 1000 cerebellopontine angle nerve sheath tumors were malignant. Objective To determine whether MPNST occurred spontaneously in NF2 by reviewing our NF2 database. Methods The prospective database consists of 1253 patients with NF2. One thousand and nine are known to be alive at last follow-up. The presence and laterality/pathology of vestibular schwannoma at diagnosis and last follow-up was sought. Results There were no cases of spontaneous MPNST with 2114 proven (n = 1150) and presumed benign (n = 964) vestibular schwannomas found. Two patients had developed MPNST (1 presumed) after having previously undergone stereotactic radiosurgery for a vestibular schwannoma. Conclusion In this series, and from the literature, malignant transformation of a vestibular schwannoma was not a feature of NF2 in the unirradiated patient. NF2 patients should not be told that they have an increased risk of malignant change in a vestibular schwannoma unless they undergo radiation treatment. However, very much larger datasets are required before it can be determined whether there is any association between NF2 and MPNST in the unirradiated patient.

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

Background Glioblastoma multiforme is the most biologically aggressive brain tumour, with only 12 month survival, despite maximum treatment. Tumour-associated macrophages and microglia (TAMM) are myeloid cells populating 30–50% of glioblastoma multiforme tumours and are identified as potential immunotherapy targets. However, characterising functional roles of TAMM subpopulations remains elusive, because of flawed mouse models and inadequate cell-surface markers. In normal rodent brain, antibody markers CD11bhi and CD45hi are proposed to highlight infiltrating monocytes, whereas CD11bhi and CD45lo cells represent microglia and differentiated peripheral macrophages. This marker-set provides conflicting results in the context of the tumour microenvironment. We redressed this issue and aimed to determine whether peripheral or central TAMMs have independent roles in glioblastoma multiforme. Methods With our non-myeloablative bone-marrow transplant model, we can replace a mouse immune system using congenic donor cells marked with green fluorescence protein (GFP) without damaging the blood-brain barrier or inadvertently activating microglia; when applying this technique we subsequently distinguish between central microglial and peripheral macrophage populations. By stereotaxic intracranial implantation of murine glioblastoma multiforme (GL261), we recapitulated the normal development of a glioblastoma multiforme tumour and performed sham intracranial injections as a comparative control. Fluorescence-activated cell sorting was done to separate TAMM subpopulations for RNA sequencing. Findings Our chimeric mouse model consistently produced 70–80% peripheral blood chimerism and overcame the issue surrounding cell-surface expression markers, distinguishing peripherally infiltrating and central tissue-resident brain cells by GFP marker status. Cerebral digestion and analysis of tumour-implanted mice revealed a novel third population (FSChi/SSChi cells) on flow cytometry that stained greater than 90% CD11b/CD45+ suggestive of TAMMs; but this cell population was absent in hemispheres of both non-tumour bearing and sham-injected mice. Interpretation Our preliminary data showed that in chimeric mice implanted with glioblastoma multiforme, peripheral cells (GFP high) were the dominant infiltrating population. With RNA extraction for downstream transcriptional analysis we aim to reliably track trafficking myeloid populations and subsequently address the ambiguity surrounding TAMMs. Thereafter, we aim to develop an immunotherapy against glioblastoma multiforme using the findings from our study. Funding None.

Background Historically neurosurgeons have accepted head injured patients only in the presence of a mass lesion requiring surgical decompression. Underpinning this is an assumption that these patients have a better outcome than patients without a surgical lesion. This has meant that many patients without a surgical lesion have been managed locally in the referring hospital. However, there is now evidence that treatment of all head injured patients in a specialist centre leads to improved outcomes. Therefore, we have asked the question: does the presence of a surgical lesion imply better outcome from severe head injury? Results We prospectively recorded the Glasgow Outcome score (GOS), at 3 months, of all the severely head injured patients treated at our institution over a two and a half year period. Of 116 patients admitted with an initial Glasgow Coma Score (GCS) of 8 or less, 58 had surgical lesions and 58 non-surgical head injuries. The two groups were well matched for presenting GCS and age. Overall our favourable outcome rate (GOS 4 and 5) at 3-months for the patients with a surgical lesion and for the non-surgical group were 47.3% and 46.6% respectively, with no significant difference between the two (P = 0.54). Conclusion The assumption in the past has always been that patients presenting in coma from traumatic diffuse brain injury will do worse than those that have a mass lesion amenable to surgical decompression. Our series would suggest that this is not the case and all severely head injured patients should expect similar outcome when cared for in a neuroscience centre.