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Background Some studies have shown a protective association between aspirin use and subarachnoid hemorrhage. Other studies have found no relationship or the reverse. These studies differ in their study populations and definitions of subarachnoid hemorrhage. Aims Our aim was to establish (1) if there is an association between aspirin and subarachnoid hemorrhage, (2) how this differs between the general population and those with intracranial aneurysms. Summary of review Studies reporting aspirin use and the occurrence of subarachnoid hemorrhage were included and grouped based on population (general population vs. aneurysm population). Odds ratios, hazard ratios, and confidence intervals were combined in random-effects models. Eleven studies were included. Overall, there was an association between aspirin and subarachnoid hemorrhage (OR 0.68 [0.48, 0.96]). However, populations were diverse and heterogeneity between studies high ( p Conclusions There is an association between aspirin use and subarachnoid hemorrhage in patients with intracranial aneurysms. This apparent protective relationship is not seen in the general population. Prospective randomized studies are required to further investigate the effect of aspirin on unruptured intracranial aneurysms.

Psychological distress is a common complication in patients after Subarachnoid haemorrhage (SAH) which often has significant impact on the prognosis. The objective of this study was to determine the pooled prevalence of anxiety symptoms and depressive symptoms in patients after SAH and identify relevant risk factors.The study adopted a systematic review and meta-analysis protocol. Multiple databases including EMBASE, Medline, PsychInfo, and Web of Science were searched for publications before 1st January 2020. Screening, data extraction, and quality assessment were undertaken following the PRISMA guidelines for preferred reporting of systematic reviews and meta-analysis. The random-effects model was used to calculate pooled prevalence rates. Meta-analysis was conducted using Comprehensive Meta-analysis software. The review protocol was registered on PROSPERO (CRD42020182594).42 studies reporting anxiety symptoms and 64 studies reporting depressive symptoms were included. The pooled short term(3 years) and long term(≥3 years) prevalence rates of anxiety symptoms were 31.4%(95% CI: 23.6%, 40.4%) and 40.4%(95% CI: 31.6%, 49.8%), respectively, whereas the pooled short term and long term prevalence rates of depressive symptoms were 25.2%(95%CI: 17.8%, 34.5%) and 35.8%(95%CI: 28.6%, 43.6%), respectively. Gender and pre-existing psychiatric conditions were identified as potential risk factors.The high prevalence of anxiety symptoms and depressive symptoms after SAH highlights the need for appropriate assessment and management of psychological stress in patients after SAH. Further research is warranted to explore potential underlying mechanisms and to develop holistic interventions that incorporate understanding of both the biological and psychological impact of SAH.

BackgroundAlthough the liquid embolic agent, Onyx, is often the preferred embolic treatment for cerebral dural arteriovenous fistulas (DAVFs), there have only been a limited number of single-center studies to evaluate its performance.ObjectiveTo carry out a multicenter study to determine the predictors of complications, obliteration, and functional outcomes associated with primary Onyx embolization of DAVFs.MethodsFrom the Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR) database, we identified patients who were treated for DAVF with Onyx-only embolization as the primary treatment between 2000 and 2013. Obliteration rate after initial embolization was determined based on the final angiographic run. Factors predictive of complete obliteration, complications, and functional independence were evaluated with multivariate logistic regression models.ResultsA total 146 patients with DAVFs were primarily embolized with Onyx. Mean follow-up was 29 months (range 0–129 months). Complete obliteration was achieved in 80 (55%) patients after initial embolization. Major cerebral complications occurred in six patients (4.1%). At last follow-up, 84% patients were functionally independent. Presence of flow symptoms, age over 65, presence of an occipital artery feeder, and preprocedural home anticoagulation use were predictive of non-obliteration. The transverse-sigmoid sinus junction location was associated with fewer complications, whereas the tentorial location was predictive of poor functional outcomes.ConclusionsIn this multicenter study, we report satisfactory performance of Onyx as a primary DAVF embolic agent. The tentorium remains a more challenging location for DAVF embolization, whereas DAVFs located at the transverse-sigmoid sinus junction are associated with fewer complications.

BACKGROUNDChronic subdural hematoma is a common neurologic disorder that is especially prevalent among older people. The effect of dexamethasone on outcomes in patients with chronic subdural hematoma has not been well studied.METHODSWe conducted a multicenter, randomized trial in the United Kingdom that enrolled adult patients with symptomatic chronic subdural hematoma. The patients were assigned in a 1:1 ratio to receive a 2-week tapering course of oral dexamethasone, starting at 8 mg twice daily, or placebo. The decision to surgically evacuate the hematoma was made by the treating clinician. The primary outcome was a score of 0 to 3, representing a favorable outcome, on the modified Rankin scale at 6 months after randomization; scores range from 0 (no symptoms) to 6 (death).RESULTSFrom August 2015 through November 2019, a total of 748 patients were included in the trial after randomization — 375 were assigned to the dexamethasone group and 373 to the placebo group. The mean age of the patients was 74 years, and 94% underwent surgery to evacuate their hematomas during the index admission; 60% in both groups had a score of 1 to 3 on the modified Rankin scale at admission. In a modified intention-to-treat analysis that excluded the patients who withdrew consent for participation in the trial or who were lost to follow-up, leaving a total of 680 patients, a favorable outcome was reported in 286 of 341 patients (83.9%) in the dexamethasone group and in 306 of 339 patients (90.3%) in the placebo group (difference, −6.4 percentage points [95% confidence interval, −11.4 to −1.4] in favor of the placebo group; P=0.01). Among the patients with available data, repeat surgery for recurrence of the hematoma was performed in 6 of 349 patients (1.7%) in the dexamethasone group and in 25 of 350 patients (7.1%) in the placebo group. More adverse events occurred in the dexamethasone group than in the placebo group.CONCLUSIONSAmong adults with symptomatic chronic subdural hematoma, most of whom had undergone surgery to remove their hematomas during the index admission, treatment with dexamethasone resulted in fewer favorable outcomes and more adverse events than placebo at 6 months, but fewer repeat operations were performed in the dexamethasone group. (Funded by the National Institute for Health Research Health Technology Assessment Programme; Dex-CSDH ISRCTN number, ISRCTN80782810. opens in new tab.)

BackgroundThe best predictor of clinical outcome after aneurysmal subarachnoid haemorrhage (aSAH) is the World Federation of Neurological Surgeons (WFNS) score. Yet, this marker of early brain injury only explains 12% of the variance in outcome. Prolonged neurotoxicity via extracellular haemoglobin (Hb) may play a role. Neurofilament light chain (NFL) is released during neuronal damage. We hypothesize that CSF NFL predicts clinical outcome after aSAH and reflects Hb-induced neurotoxicity.MethodsCSF was collected via an external ventricular drain from 44 high-grade aSAH patients over 14 days post-ictus, and via lumbar puncture from 11 non-haemorrhagic, non-inflammatory neurologi- cal control patients. NFL and Hb were measured using enzyme-linked immunosorbent assay and ultra- performance liquid chromatography respectively. Clinical outcome after aSAH was assessed using the modified Rankin Score (mRS).ResultsNFL was higher in aSAH versus control CSF. High CSF NFL and high WFNS independently predicted worse mRS. CSF NFL was a stronger predictor than WFNS. Post-ictus, NFL and Hb CSF concentration gradually increased over two weeks. Maximum CSF NFL was correlated with maximum preceding CSF Hb, but not WFNS.ConclusionThe biomarker NFL is a predictor of clinical outcome after aSAH. NFL concentration likely reflects delayed Hb-induced neurotoxicity rather than early brain injury.pg1p07@soton.ac.uk

BACKGROUND There are many questions that remain unanswered regarding outcomes following cranioplasty including the timing of cranioplasty following craniectomy as well as the material used. OBJECTIVE To establish and evaluate 30-d outcomes for all cranial reconstruction procedures in the United Kingdom (UK) and Ireland through a prospective multicenter cohort study. METHODS Patients undergoing cranioplasty insertion or revision between June 1, 2019 and November 30, 2019 in 25 neurosurgical units were included. Data collected include demographics, craniectomy date and indication, cranioplasty material and date, and 30-d outcome. RESULTS In total, 313 operations were included, consisting of 255 new cranioplasty insertions and 58 revisions. Of the new insertions, the most common indications for craniectomy were traumatic brain injury (n = 110, 43%), cerebral infarct (n = 38, 15%), and aneurysmal subarachnoid hemorrhage (n = 30, 12%). The most common material was titanium (n = 163, 64%). Median time to cranioplasty was 244 d (interquartile range 144-385), with 37 new insertions (15%) within or equal to 90 d. In 30-d follow-up, there were no mortalities. There were 14 readmissions, with 10 patients sustaining a wound infection within 30 d (4%). Of the 58 revisions, the most common reason was due to infection (n = 33, 59%) and skin breakdown (n = 13, 23%). In 41 (71%) cases, the plate was removed during the revision surgery. CONCLUSION This study is the largest prospective study of cranioplasty representing the first results from the UK Cranial Reconstruction Registry, a first national registry focused on cranioplasty with the potential to address outstanding research questions for this procedure.

Background Current evidence suggests that intracranial dural arteriovenous fistulas (dAVFs) lacking cortical venous drainage (CVD) have a benign clinical course. However, there is no large study evaluating the safety/efficacy of current treatments and their impact over the natural history of no-CVD dAVFs. Methods We conducted an analysis of the retrospectively collected multi-center Consortium for dAVF Outcomes Research (CONDOR) database. Demographics, presenting symptoms, dAVFs’ angiographic features and therapeutic intervention/complications data of patients with Borden-Shucart type 1 dAVFs were reviewed. Clinical and radiological follow-up information was assessed to determine rates of new intracranial hemorrhage or non-hemorrhagic neurological deficit (NHND), worsening of venous hyperdynamic symptoms (VHS), angiographic recurrence, progression or spontaneous regression of dAVFs over time. Results A total of 368 patients/Borden-Shucart type I dAVFs were identified. For patients with multiple dAVFs, only the largest one was included in the analysis. Mean age was 57.9±15.6 years, and 60.9% were women. Mean follow-up time was 40.1±45.2 months. The most common location was the transverse/sigmoid sinus (50.3%). Of 240 treated dAVFs, 224 (93.3%) underwent endovascular embolization, 11 (4.9%) radiosurgery alone and 5 (2.1%) open surgery as primary modality. After first embolization, most dAVFs (45.5%) achieved only partial reduction in early venous filling. Multiple complementary interventions increased complete obliteration rates from 37.5% after first embolization to 45.5% after 2 or more embolizations, and 53.8% after complimentary radiosurgery/open surgery. Immediate post-procedural complications occurred in 38 treated dAVFs (15.8%) and 7 with permanent sequelae. Of 129 completely obliterated dAVFs by any therapeutic modality, 3 (2.3%) showed angiographic recurrence/recanalization in a mean time of 10 months after treatment. Progression to Borden-Shucart types II-III was documented in 2.4% and subsequent development of new dAVF in 1.5%. Partial spontaneous regression was found in 24 out of 115 non-treated dAVFs with follow-up available (20.9%). Multivariate Cox regression analysis demonstrated that NHND or severe VHS at presentation and infratentorial location were associated with worse prognosis. Kaplan-Meier curves demonstrated no significant difference for stable/improved symptoms survival probability in treated versus non-treated dAVFs. However, estimated survival times showed better trends for treated dAVFs compared with non-treated dAVFs (179.2 months vs 163 months, Log-rank p-value = 0.12). This difference was statistically significant for treated dAVFs with 100% occlusion compared with partially-occluded dAVFs (173.2 months vs 143.9 months, Log-rank p-value Conclusion Current therapeutic modalities for management of dAVFs without CVD are safe and may provide better symptom control when complete angiographic occlusion can be achieved. Disclosures E. Samaniego: 1; C; SVIN 2019, Bee Foundation 2019. 2; C; Medtronic, MicroVention. J. Roa: None. M. Hayakawa: None. S. Ortega-Gutierrez: 2; C; Stryker, Medtronic. R. Guniganti: None. D. Bulters: None. A. Alaraj: None. S. Amin-Hanjani: None. G. Lanzino: None. G. Zipfel: None. D. Hasan: None. C. Derdeyn: None.

OBJECTIVE The risk-to-benefit profile of treating an unruptured high-grade dural arteriovenous fistula (dAVF) is not clearly defined. The aim of this multicenter retrospective cohort study was to compare the outcomes of different interventions with observation for unruptured high-grade dAVFs. METHODS The authors retrospectively reviewed dAVF patients from 12 institutions participating in the Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR). Patients with unruptured high-grade (Borden type II or III) dAVFs were included and categorized into four groups (observation, embolization, surgery, and stereotactic radiosurgery [SRS]) based on the initial management. The primary outcome was defined as the modified Rankin Scale (mRS) score at final follow-up. Secondary outcomes were good outcome (mRS scores 0–2) at final follow-up, symptomatic improvement, all-cause mortality, and dAVF obliteration. The outcomes of each intervention group were compared against those of the observation group as a reference, with adjustment for differences in baseline characteristics. RESULTS The study included 415 dAVF patients, accounting for 29, 324, 43, and 19 in the observation, embolization, surgery, and SRS groups, respectively. The mean radiological and clinical follow-up durations were 21 and 25 months, respectively. Functional outcomes were similar for embolization, surgery, and SRS compared with observation. With observation as a reference, obliteration rates were higher after embolization (adjusted OR [aOR] 7.147, p = 0.010) and surgery (aOR 33.803, p < 0.001) and all-cause mortality was lower after embolization (imputed, aOR 0.171, p = 0.040). Hemorrhage rates per 1000 patient-years were 101 for observation versus 9, 22, and 0 for embolization (p = 0.022), surgery (p = 0.245), and SRS (p = 0.077), respectively. Nonhemorrhagic neurological deficit rates were similar between each intervention group versus observation. CONCLUSIONS Embolization and surgery for unruptured high-grade dAVFs afforded a greater likelihood of obliteration than did observation. Embolization also reduced the risk of death and dAVF-associated hemorrhage compared with conservative management over a modest follow-up period. These findings support embolization as the first-line treatment of choice for appropriately selected unruptured Borden type II and III dAVFs.

Two of the key functions of arteries in the brain are (1) the well‐recognized supply of blood via the vascular lumen and (2) the emerging role for the arterial walls as routes for the elimination of interstitial fluid (ISF) and soluble metabolites, such as amyloid beta (Aβ), from the brain and retina. As the brain and retina possess no conventional lymphatic vessels, fluid drainage toward peripheral lymph nodes is mediated via transport along basement membranes in the walls of capillaries and arteries that form the intramural peri‐arterial drainage (IPAD) system. IPAD tends to fail as arteries age but the mechanisms underlying the failure are unclear. In some people this is reflected in the accumulation of Aβ plaques in the brain in Alzheimer's disease (AD) and deposition of Aβ within artery walls as cerebral amyloid angiopathy (CAA). Knowledge of the dynamics of IPAD and why it fails with age is essential for establishing diagnostic tests for the early stages of the disease and for devising therapies that promote the clearance of Aβ in the prevention and treatment of AD and CAA. This editorial is intended to introduce the rationale that has led to the establishment of the Clearance of Interstitial Fluid (ISF) and CSF (CLIC) group, within the Vascular Professional Interest Area of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment.

Background and Purpose: Given the benign natural history of intracranial low-grade dural arteriovenous fistulas (dAVFs), their routine treatment remains controversial. The aim of this study is to compare the outcomes of low-grade dAVF treatment to conservative management. Methods: We performed a retrospective review of dAVF patients derived from 12 institutions participating in the Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR). Patients with low-grade (Borden I) dAVFs were included and categorized into treatment and observation cohorts. Primary outcome was defined as modified Rankin Scale (mRS) score at final follow-up. Secondary outcomes were rates of excellent (mRS 0-1) and good (mRS 0-2) functional outcomes, symptomatic improvement, mortality, and obliteration at final follow-up. Results: The treatment and observation cohorts comprised 230 and 112 patients, respectively. At last follow up, no difference in primary or secondary outcomes was observed between the two cohorts, with the exception of obliteration, which was higher in the treatment cohort (79.3% vs. 28.2%, p Conclusions: Low-grade dAVF treatment was not associated with increased functional disability compared to conservative management. Although higher obliteration rates were achieved in the treatment cohort, rates of symptomatic improvement were similar between the two cohorts. This study did not provide evidence to support the routine treatment of low-grade dAVFs.

Traumatic brain injury (TBI) is a leading cause of death and disability globally. No drug treatments are available, so interest has turned to endogenous neural stem cells (NSCs) as alternative strategies for treatment. We hypothesized that regulation of cell proliferation through modulation of the sonic hedgehog pathway, a key NSC regulatory pathway, could lead to functional improvement. We assessed sonic hedgehog (Shh) protein levels in the cerebrospinal fluid (CSF) of patients with TBI. Using the cortical contusion injury (CCI) model in rodents, we used pharmacological modulators of Shh signaling to assess cell proliferation within the injured cortex using the marker 5-Ethynyl-2’-deoxyuridine (EdU); 50mg/mL. The phenotype of proliferating cells was determined and quantified. Motor function was assessed using the rotarod test. In patients with TBI there is a reduction of Shh protein in CSF compared with control patients. In rodents, following a severe CCI, quiescent cells become activated. Pharmacologically modulating the Shh signaling pathway leads to changes in the number of newly proliferating injury-induced cells. Upregulation of Shh signaling with Smoothened agonist (SAG) results in an increase of newly proliferating cells expressing glial fibrillary acidic protein (GFAP), whereas the Shh signaling inhibitor cyclopamine leads to a reduction. Some cells expressed doublecortin (DCX) but did not mature into neurons. The SAG-induced increase in proliferation is associated with improved recovery of motor function. Localized restoration of Shh in the injured rodent brain, via increased Shh signaling, has the potential to sustain endogenous cell proliferation and the mitigation of TBI-induced motor deficits albeit without the neuronal differentiation.

The molecular processes underlying the ageing-related decline in cognitive performance and memory observed in humans are poorly understood. Studies in rodents have shown that N-methyl-D-aspartate receptors (NMDARs) containing GluN2B subunits can enhance the ability of synapses to undergo long term potentiation. In ageing rodents, the contribution of GluN2B to synaptic function is reduced compared to younger animals and the decline in GluN2B subunit expression is correlated with impaired memory functions. However, the contribution of GluN2B containing receptors to synaptic transmission in cortical synapses has not been previously studied. We investigated the synaptic contribution of GluN2A and GluN2B containing NMDARs in adult human neurons using fresh non-pathological temporal cortical tissue resected during neurosurgical procedures. The tissue we obtained fulfilled quality criteria by the absence of inflammation markers and proteomic degradation. We show an age-dependent decline in the NMDA/AMPA receptor ratio in adult human temporal cortical synapses. We demonstrate that GluN2B containing NMDA receptors contribute to synaptic responses in the adult human brain with a reduced contribution in older individuals. With previous evidence demonstrating the critical role of synaptic GluN2B in regulating synaptic strength and memory storage in mice, this progressive reduction of GluN2B in the human brain during aging may underlie a molecular mechanism in the age-related decline in cognitive abilities and memory observed in humans.

After subarachnoid haemorrhage, prolonged exposure to toxic extracellular haemoglobin occurs in the brain. Here, we investigate the role of haemoglobin neurotoxicity in vivo and its prevention. In humans after subarachnoid haemorrhage, haemoglobin in cerebrospinal fluid was associated with neurofilament light chain, a marker of neuronal damage. Most haemoglobin was not complexed with haptoglobin, an endogenous haemoglobin scavenger present at very low concentration in the brain. Exogenously added haptoglobin bound most uncomplexed haemoglobin, in the first 2 weeks after human subarachnoid haemorrhage, indicating a wide therapeutic window. In mice, the behavioural, vascular, cellular and molecular changes seen after human subarachnoid haemorrhage were recapitulated by modelling a single aspect of subarachnoid haemorrhage: prolonged intrathecal exposure to haemoglobin. Haemoglobin-induced behavioural deficits and astrocytic, microglial and synaptic changes were attenuated by haptoglobin. Haptoglobin treatment did not attenuate large-vessel vasospasm, yet improved clinical outcome by restricting diffusion of haemoglobin into the parenchyma and reducing small-vessel vasospasm. In summary, haemoglobin toxicity is of clinical importance and preventable by haptoglobin, independent of large-vessel vasospasm.

Background Patient selection for seizure prophylaxis after traumatic brain injury (TBI) and duration of anti-epileptic drug treatment for patients with early post-traumatic seizures (PTS), remain plagued with uncertainty. In early 2017, a collaborative group of neurosurgeons, neurologists, neurointensive care and rehabilitation medicine physicians was formed in the UK with the aim of assessing variability in current practice and gauging the degree of uncertainty to inform the design of future studies. Here we present the results of a survey of clinicians managing patients with TBI in the UK and Ireland. Materials and methods An online survey was developed and piloted. Following approval by the Academic Committee of the Society of British Neurological Surgeons, it was distributed via appropriate electronic mailing lists. Results One hundred and seventeen respondents answered the questionnaire, predominantly neurosurgeons (76%) from 30 (of 32) trauma-receiving hospitals in the UK and Ireland. Fifty-three percent of respondents do not routinely use seizure prophylaxis, but 38% prescribe prophylaxis for one week. Sixty percent feel there is uncertainty regarding the use of seizure prophylaxis, and 71% would participate in further research to address this question. Sixty-two percent of respondents use levetiracetam for treatment of seizures during the acute phase, and 42% continued for a total of 3 months. Overall, 90% were uncertain about the duration of treatment for seizures, and 78% would participate in further research to address this question. Conclusion The survey results demonstrate the variation in practice and uncertainty in both described aspects of management of patients who have suffered a TBI. The majority of respondents would want to participate in future research to help try and address this critical issue, and this shows the importance and relevance of these two clinical questions. Electronic supplementary material The online version of this article (10.1007/s00701-018-3683-9) contains supplementary material, which is available to authorized users.

Haemoglobin is released into the CNS during the breakdown of red blood cells after intracranial bleeding. Extracellular free haemoglobin is directly neurotoxic. Haemoglobin scavenging mechanisms clear haemoglobin and reduce toxicity; these mechanisms include erythrophagocytosis, haptoglobin binding of haemoglobin, haemopexin binding of haem and haem oxygenase breakdown of haem. However, the capacity of these mechanisms is limited in the CNS, and they easily become overwhelmed. Targeting of haemoglobin toxicity and scavenging is, therefore, a rational therapeutic strategy. In this Review, we summarize the neurotoxic mechanisms of extracellular haemoglobin and the peculiarities of haemoglobin scavenging pathways in the brain. Evidence for a role of haemoglobin toxicity in neurological disorders is discussed, with a focus on subarachnoid haemorrhage and intracerebral haemorrhage, and emerging treatment strategies based on the molecular pathways involved are considered. By focusing on a fundamental biological commonality between diverse neurological conditions, we aim to encourage the application of knowledge of haemoglobin toxicity and scavenging across various conditions. We also hope that the principles highlighted will stimulate research to explore the potential of the pathways discussed. Finally, we present a consensus opinion on the research priorities that will help to bring about clinical benefits.

Aβ, amyloid beta, CAA, cerebral amyloid angiopathy, CT, computed tomographic scanning, IPAD, intramural periarterial drainage, ISF, interstitial fluid, MRI, magnetic resonance imaging, PVS, perivascular spaces, WMH, white matter hyperintensities.Cerebral white matter hyperintensities (WMH) observed on magnetic resonance imaging (MRI), or low attenuation on computed tomographic scanning (CT), are the most frequent brain imaging finding in patients with small vessel disease or dementia. It has been assumed that WMH are due to arteriosclerosis or blood-brain barrier breakdown, though recently it was demonstrated that WMH have distinct molecular signatures in Alzheimer's disease (AD) where markers of Wallerian degeneration are present, compared to normal ageing [1]. This article is protected by copyright. All rights reserved.

The Wessex Modified Richmond Sedation Scale (WMRSS) has been developed with the aim of improving the early identification of patients requiring decompressive hemicraniectomy for malignant middle cerebral artery syndrome (MMS). The objective of this study was to evaluate the WMRSS against the Glasgow Coma Scale (GCS). A retrospective study was conducted of patients admitted to our unit for observation of MMS. Data were obtained on WMRSS and GCS recordings from admission up to 120-h post-ictus. Patients’ meeting inclusion criteria were recommended for theatre based on subsequent deteriorations in consciousness on either WMRSS or GCS from a 6-h post-stroke baseline, after ruling out non-neurological causes. Approximately, 60% of those eligible for monitoring were not recommended for theatre, and none died; however, these patients continued to demonstrate some variability in recorded conscious level. Patients requiring surgical intervention showed earlier drops in WMRSS compared to GCS. Neither the GCS nor the WMRSS on admission predicted the subsequent need for decompressive surgery. There was no increase in mortality with the introduction of WMRSS. WMRSS adds value to monitoring MMS by indicating need for surgery prior to GCS. Early reduction in consciousness may not be sufficient for proceeding to surgical intervention, but subsequent reduction in consciousness may be a more appropriate criterion for surgery.

Background External ventricular drain (EVD) dislodgement is common and leads to significant morbidity and mortality. Many securement techniques to prevent this are described. There are, however, no objective studies comparing them. This study aimed to determine the most secure method of securing an EVD. Methods A survey was distributed through the British Neurosurgical Trainee Research Collaborative to determine common EVD securement methods and select techniques for testing. Securement methods were tested in a pig cadaver model. Peak pull force before EVD failure was measured. Failure was defined as catheter displacement 1 cm from the insertion site, catheter fracture, or suture fracture. Results Twenty-three neurosurgical units responded. Five basic EVD securement methods were in common use. These were tested in isolation and in combination so that in total 15 common methods were tested. The most secure method was a triple construct, consisting of an anchoring suture, sutures around a coil of the catheter, and either a soft plastic flange (25.85 N, 95% confidence interval 24.95 N–26.75 N) or a hard plastic flange (29.05 N, 95% confidence interval 25.69 N–32.41 N). Of the individual methods, single anchoring sutures, soft flanges, VentriFix, and staples were found to be the least secure, whereas multiple sutures and hard flanges were the most secure. Conclusions An anchoring suture followed by a coil of the catheter and finally a flange is the most secure method for securing EVDs. This simple technique can withstand up to 8.2 times the force of a single anchoring suture, is easily used, and decreases the likelihood of EVD dislodgement and associated complications.

Cerebral autoregulation (CA) refers to the ability of the brain vasculature to control blood flow in the face of changing blood pressure. One of the methods commonly used to assess cerebral autoregulation, especially in participants at rest, is the analysis of phase derived from transfer function analysis (TFA), relating arterial blood pressure (ABP) to cerebral blood flow (CBF). This and other indexes of CA can provide consistent results when comparing groups of subjects (e.g. patients and healthy controls or normocapnia and hypercapnia) but can be quite variable within and between individuals. The objective of this paper is to present a novel parametric bootstrap method, used to estimate the sampling distribution and hence confidence intervals (CIs) of the mean phase estimate in the low-frequency band, in order to optimise estimation of measures of CA function and allow more robust inferences on the status of CA from individual recordings. A set of simulations was used to verify the proposed method under controlled conditions. In 20 healthy adult volunteers (age 25.53.5 years), ABP and CBF velocity (CBFV) were measured at rest, using a Finometer device and Transcranial Doppler (applied to the middle cerebral artery), respectively. For each volunteer, five individual recordings were taken on different days, each approximately 18 min long. Phase was estimated using TFA. Analysis of recorded data showed widely changing CIs over the duration of recordings, which could be reduced when noisy data and frequencies with low coherence were excluded from the analysis (Wilcoxon signed rank test p = 0.0065). The TFA window-lengths of 50s gave smaller CIs than lengths of 100s (p < 0.001) or 20s (p < 0.001), challenging the usual recommendation of 100s. The method adds a much needed flexible statistical tool for CA analysis in individual recordings.

Background Long-term outcomes following occlusion of spinal dural arteriovenous fistula (SDAVF) are poorly understood and are based on small series reporting predominantly short-term outcomes. The degree and duration of improvement remain unclear. In this study, we analyzed long-term outcomes following occlusion in a cohort of patients with SDAVF. Methods This was a single-center cohort study of patients with SDAVF identified from a prospective database. Outcomes were assessed using a modified Aminoff and Logue Disability (ALD) Scale, the modified Rankin Scale (mRS), and patient-reported outcomes at presentation and long-term follow-up. Both angiographic recanalization and idiopathic functional recurrence rates were calculated. Results Of the total of 67 patients with SAVDF identified, 59 were eligible for inclusion in this study. Fifty-seven of these 59 (97%) underwent occlusion. Twenty-two patients underwent initial embolization; 12 were occluded. Two patients recanalized. Eleven patients underwent surgery after attempted embolization; 10 were occluded. Thirty-seven patients treated by surgery only were occluded. The median duration of follow-up was 63 months (range, 12–240 months). After occlusion, the ALD gait and urinary scores improved by a median of 1 point. Although the median mRS score was unchanged, 49% of the patients experienced improvement, most by 1 point. There was no difference between the patients occluded by embolization or surgery, but those requiring both approaches had worse gait and urinary scores (P = 0.005 and 0.03, respectively). The duration of symptoms by itself had no effect on outcomes (P = 0.61). Following occlusion, 5 patients experienced an idiopathic late functional deterioration. Of 16 patients presenting with paraplegia, 13 (81%) improved, with a median mRS improvement of 1 point. Conclusions Following occlusion, patients with SDAVF experienced a modest improvement in symptoms, most commonly by 1 point on the ALD scale. Idiopathic late deterioration was seen in 9.1% of patients.

Background Effective mentoring is an invaluable element in the development of next generation of neurosurgeons. A mentor helps to develop professional core values, technical and non-technical skills, attitudes and disposition required to be qualified and competent neurosurgeon. Giving the invaluable significance of mentoring in neurosurgery, we undertook this literature review to identify mentoring models evaluating its success and relative benefit. Methods Literature search identified using MeSH word ‘mentor’, mentoring, mentorship, mentoring model, neurosurgery’ in MEDLINE, EMBASE and Scopus databases from 1990 to 2016. Literature reviewed to identify status of mentoring in neurosurgery, potential barriers, pitfalls and future framework for mentoring in neurosurgery. Additional articles identified through manual search of reference lists. Results A total of 247 studies were obtained from electronic databases, after removing duplicates, abstracts, letters to the editor and non-neurosurgery papers. Sixteen full text articles retrieved out of which five met the inclusion criteria. Generally, there is paucity of articles regarding mentoring in neurosurgery, all included papers were written in English Language, all of them described mentoring model used including simulation, distance, collaborative, facilitative tele-mentoring and peer mentoring. Conclusion Mentoring in Neurosurgery is an important aspect of personal and professional development of neurosurgical trainees, currently there is decline in traditional apprenticeship due to increase demand for modern use of specialised technology, simulation and tele-medicine in neurosurgery practice. Effective and efficient mentoring will be an interplay of six mentoring models (collaborative, facilitative, distance, simulation, tele mentoring and peer mentoring) identified.

Recovery of oculomotor nerve palsy after microsurgical and endovascular treatment has been studied in numerous small series of predominantly ruptured aneurysms. Little consideration has been given to the distinction between ruptured and unruptured aneurysms. This study examines the influence of treatment modality on oculomotor palsy recovery as a result of unruptured posterior communicating artery aneurysms.Patients who presented between 2003 and 2015 with an oculomotor palsy secondary to an unruptured posterior communicating artery aneurysm were identified from the hospital database. A keyword search for "posterior communicating artery aneurysm" and "oculomotor nerve palsy OR third nerve palsy" using the PubMed database was performed for the narrative review.The cohort study and narrative review identified 15 and 179 eligible patients, respectively. Surgically treated patients in the cohort study did not have a significantly better rate of complete palsy resolution than those who had been coiled (P = 0.08). In the review, clipping of the aneurysm resulted in a higher rate of complete palsy resolution (70.0%; 95% confidence interval [CI], 60.7%-79.3%) than did coiling (46.5%; 95% CI, 36.0%-57.0%). Patients who presented with an aneurysm7 mm had a higher rate of complete palsy resolution compared with aneurysms7 mm (68.6%; 95% CI, 57.7%-79.5% vs. 44.3%; 95% CI, 32.7%-55.9%). Patients presenting with a complete palsy (49.4%; 95% CI, 38.6%-60.2%) had a lower rate of recovery than did those with a partial palsy (71.4%; 95% CI, 60.2%-82.6%).In this narrative review, surgical clipping of unruptured posterior communicating artery aneurysms was associated with a higher rate of associated oculomotor palsy recovery than was endovascular treatment.

OBJECTIVESymptomatic chronic subdural hematoma (CSDH) will become an increasingly common presentation in neurosurgical practice as the population ages, but quality evidence is still lacking to guide the optimal management for these patients. The British Neurosurgical Trainee Research Collaborative (BNTRC) was established by neurosurgical trainees in 2012 to improve research by combining the efforts of trainees in each of the United Kingdom (UK) and Ireland's neurosurgical units (NSUs). The authors present the first study by the BNTRC that describes current management and outcomes for patients with CSDH throughout the UK and Ireland. This provides a resource both for current clinical practice and future clinical research on CSDH.METHODSData on management and outcomes for patients with CSDH referred to UK and Ireland NSUs were collected prospectively over an 8-month period and audited against criteria predefined from the literature: NSU mortality < 5%, NSU morbidity < 10%, symptomatic recurrence within 60 days requiring repeat surgery < 20%, and unfavorable functional status (modified Rankin Scale score of 4–6) at NSU discharge < 30%.RESULTSData from 1205 patients in 26 NSUs were collected. Bur-hole craniostomy was the most common procedure (89%), and symptomatic recurrence requiring repeat surgery within 60 days was observed in 9% of patients. Criteria on mortality (2%), rate of recurrence (9%), and unfavorable functional outcome (22%) were met, but morbidity was greater than expected (14%). Multivariate analysis demonstrated that failure to insert a drain intraoperatively independently predicted recurrence and unfavorable functional outcome (p = 0.011 and p = 0.048, respectively). Increasing patient age (p < 0.00001), postoperative bed rest (p = 0.019), and use of a single bur hole (p = 0.020) independently predicted unfavorable functional outcomes, but prescription of high-flow oxygen or preoperative use of antiplatelet medications did not.CONCLUSIONSThis is the largest prospective CSDH study and helps establish national standards. It has confirmed in a real-world setting the effectiveness of placing a subdural drain. This study identified a number of modifiable prognostic factors but questions the necessity of some common aspects of CSDH management, such as enforced postoperative bed rest. Future studies should seek to establish how practitioners can optimize perioperative care of patients with CSDH to reduce morbidity as well as minimize CSDH recurrence. The BNTRC is unique worldwide, conducting multicenter trainee-led research and audits. This study demonstrates that collaborative research networks are powerful tools to interrogate clinical research questions.

BACKGROUND: Only a minority of intracranial aneurysms rupture to cause subarachnoid hemorrhage. OBJECTIVE: To test the hypothesis that unruptured aneurysms have different characteristics and risk factor profiles compared to ruptured aneurysms. METHODS: We recruited patients with unruptured aneurysms or aneurysmal subarachnoid hemorrhages at 22 UK hospitals between 2011 and 2014. Demographic, clinical, and imaging data were collected using standardized case report forms. We compared risk factors using multivariable logistic regression. RESULTS: A total of 2334 patients (1729 with aneurysmal subarachnoid hemorrhage, 605 with unruptured aneurysms) were included (mean age 54.22 yr). In multivariable analyses, the following variables were independently associated with rupture status: black ethnicity (odds ratio [OR] 2.42; 95% confidence interval [CI] 1.29-4.56, compared to white) and aneurysm location (anterior cerebral artery/anterior communicating artery [OR 3.21; 95% CI 2.34-4.40], posterior communicating artery [OR 3.92; 95% CI 2.67-5.74], or posterior circulation [OR 3.12; 95% CI 2.08-4.70], compared to middle cerebral artery). The following variables were inversely associated with rupture status: antihypertensive medication (OR 0.65; 95% CI 0.49-0.84), hypercholesterolemia (0.64 OR; 95% CI 0.48-0.85), aspirin use (OR 0.28; 95% CI 0.20-0.40), internal carotid artery location (OR 0.53; 95% CI 0.38-0.75), and aneurysm size (per mm increase; OR 0.76; 95% CI 0.69-0.84). CONCLUSION: We show substantial differences in patient and aneurysm characteristics between ruptured and unruptured aneurysms. These findings support the hypothesis that different pathological mechanisms are involved in the formation of ruptured aneurysms and incidentally detected unruptured aneurysms. The potential protective effect of aspirin might justify randomized prevention trials in patients with unruptured aneurysms.

Background Aneurysmal hemorrhage induced cerebral vasospasm; delayed ischemic neurologic deficit (DIND), poor neurologic outcome, and mortality are major causes of mortality and morbidity. The effects of cholesterol-lowering agents in these patients remain controversial. This up-to-date systematic review and meta-analysis aimed to evaluate the efficacy of statin use in patients with aneurysmal subarachnoid hemorrhage. Methods A systematic review of the literature conducted using electronic database searched up to September 2016 included Cochrane Central Register of Controlled Trials in the Cochrane Library, Medline, Embase, and Science Citation Index Expanded database to identify relevant studies. Data were extracted and critically appraised by 3 independent authors. In addition, fixed or random-effects model were applied to calculated pooled results based on degree of heterogeneity. Results Ten randomized controlled trials were identified with 1214 patients; 587 patients received statins and there were 627 patients in the placebo group. Statins were found to significantly reduce cerebral vasospasm (odds ratio [OR], 0.46; 95% confidence interval [CI], 0.28–0.78, P = 0.002) and DIND (OR, 0.72; 95% CI, 0.54–0.97; P = 0.03). However, there was no significant decrease in mortality (OR, 0.77; 95% CI, 0.54–1.11; P = 0.16) and poor neurologic outcome (OR, 0.96; 95% CI, 0.75–1.23; P = 0.74). Conclusions The outcome of this meta-analysis showed that use of statins in aneurysmal subarachnoid hemorrhage might have the potential to decrease occurrence of vasospasm and DIND. However, there was no benefit in the reduction of mortality and poor neurologic outcome. This is a call for further research.

Haptoglobin (Hp) is a plasma protein involved in clearing extracellular haemoglobin and regulating inflammation; it exists as two genetic variants (Hp1 and Hp2). In a meta-analysis of six published studies, we confirm that Hp genotype affects short-term outcome (cerebral vasospasm and/or delayed cerebral ischemia) after subarachnoid haemorrhage (SAH) but not long-term outcome (Glasgow Outcome Score and modified Rankin Scale between one and three months). A closer examination of the heterozygous group revealed that the short-term outcome of Hp2-1 individuals clustered with that of Hp1-1 and not Hp2-2, suggesting that the presence of one Hp1 allele was sufficient to confer protection. Since the presence of the Hp dimer is the only common feature between Hp1-1 and Hp2-1 individuals, the absence of this Hp moiety is most likely to underlie vasospasm in Hp2-2 individuals. These results have implications for prognosis after SAH and will inform further research into Hp-based mechanism of action and treatment.

Summary Background Insertion of a ventriculoperitoneal shunt for hydrocephalus is one of the commonest neurosurgical procedures worldwide. Infection of the implanted shunt affects up to 15% of these patients, resulting in prolonged hospital treatment, multiple surgeries, and reduced cognition and quality of life. Our aim was to determine the clinical and cost-effectiveness of antibiotic (rifampicin and clindamycin) or silver shunts compared with standard shunts at reducing infection. Methods In this parallel, multicentre, single-blind, randomised controlled trial, we included patients with hydrocephalus of any aetiology undergoing insertion of their first ventriculoperitoneal shunt irrespective of age at 21 regional adult and paediatric neurosurgery centres in the UK and Ireland. Patients were randomly assigned (1:1:1 in random permuted blocks of three or six) to receive standard shunts (standard shunt group), antibiotic-impregnated (0·15% clindamycin and 0·054% rifampicin; antibiotic shunt group), or silver-impregnated shunts (silver shunt group) through a randomisation sequence generated by an independent statistician. All patients and investigators who recorded and analysed the data were masked for group assignment, which was only disclosed to the neurosurgical staff at the time of operation. Participants receiving a shunt without evidence of infection at the time of insertion were followed up for at least 6 months and a maximum of 2 years. The primary outcome was time to shunt failure due the infection and was analysed with Fine and Gray survival regression models for competing risk by intention to treat. This trial is registered with ISRCTN 49474281. Findings Between June 26, 2013, and Oct 9, 2017, we assessed 3505 patients, of whom 1605 aged up to 91 years were randomly assigned to receive either a standard shunt (n=536), an antibiotic-impregnated shunt (n=538), or a silver shunt (n=531). 1594 had a shunt inserted without evidence of infection at the time of insertion (533 in the standard shunt group, 535 in the antibiotic shunt group, and 526 in the silver shunt group) and were followed up for a median of 22 months (IQR 10–24; 53 withdrew from follow-up). 32 (6%) of 533 evaluable patients in the standard shunt group had a shunt revision for infection, compared with 12 (2%) of 535 evaluable patients in the antibiotic shunt group (cause-specific hazard ratio [csHR] 0·38, 97·5% CI 0·18–0·80, p=0·0038) and 31 (6%) of 526 patients in the silver shunt group (0·99, 0·56–1·74, p=0·96). 135 (25%) patients in the standard shunt group, 127 (23%) in the antibiotic shunt group, and 134 (36%) in the silver shunt group had adverse events, which were not life-threatening and were mostly related to valve or catheter function. Interpretation The BASICS trial provides evidence to support the adoption of antibiotic shunts in UK patients who are having their first ventriculoperitoneal shunt insertion. This practice will benefit patients of all ages by reducing the risk and harm of shunt infection. Funding UK National Institute for Health Research Health Technology Assessment programme.

The first part of this chapter describes normal neurovascular anatomy including its embryology, histology, and normal arterial variants. It includes angiographic arterial anatomy and also the structures and territories supplied by specific vessels. The anatomy of the venous sinuses and both the superficial and deep cerebral veins are described. The second part details normal cerebral neurophysiology, including autoregulation and the control of cerebral perfusion. It covers the myogenic, metabolic, and neurogenic mechanisms of cerebral blood flow and vessel diameter regulation. Finally, the role and influence of mannitol on cerebral blood flow is described, and how although it acutely reduces cerebral volume and intracranial pressure, its exact mechanism of action remains unclear.

Glutamate receptors of the N-methyl-D-aspartate (NMDA) family are coincident detectors of pre- and postsynaptic activity, allowing Ca2+ influx into neurons. These properties are central to neurological disease mechanisms and are proposed to be the basis of associative learning and memory. In addition to the well-characterised canonical GluN2A NMDAR isoform, large-scale open reading frames in human tissues had suggested the expression of a primate-specific short GluN2A isoform referred to as GluN2A-S. Here, we confirm the expression of both GluN2A transcripts in human and primate but not rodent brain tissue, and show that they are translated to two corresponding GluN2A proteins present in human brain. Furthermore, we demonstrate that recombinant GluN2A-S co-assembles with the obligatory NMDAR subunit GluN1 to form functional NMDA receptors. These findings suggest a more complex NMDAR repertoire in human brain than previously thought.

Objectives\ud External ventricular drain (EVD) placement is required frequently in neurosurgical patients to divert cerebrospinal fluid and monitor intracranial pressure. The usual practice is the tunneled EVD technique performed in operating theaters. EVD insertion through a bolt in intensive care also is described. We employ both practices in our institute. Herein, we compare the indications, accuracy, safety, and costs of the 2 techniques.\ud \ud Methods\ud This was a retrospective cohort study of a prospectively maintained EVD database of all patients undergoing first frontal EVD placement between January 2010 and December 2015. Those patients with preceding cerebrospinal fluid infection were excluded. We compared bolt EVD with tunneled EVD techniques in terms of accuracy of EVD tip location by analyzing computed tomography scans to grade catheter tip location as optimal (ipsilateral frontal horn) or otherwise suboptimal, and complications that include infection and revision rates.\ud \ud Results\ud In total, 579 eligible patients aged 3 months to 84 years were identified; 430 had tunneled EVDs and 149 bolt EVDs. The most frequent diagnosis was intracranial hemorrhage (73% bolt vs. 50.4% tunneled group; P < 0.001). Other diagnoses included tumor (4.7% bolt vs. 19.1% tunneled; P < 0.001) and traumatic brain injury (17.5% bolt vs. 17.4% tunneled). In the bolt EVD group 66.4% of EVD tips were optimal, compared with 61.0% in the tunneled group (P = 0.33). Infection was confirmed in 15 (10.0%) bolt EVDs compared with 61 (14.2%) tunneled EVDs (P = 0.2). Each bolt EVD kit costs £260, whereas placing a tunneled one in the theater costs £1316.\ud \ud Conclusions\ud Bedside bolt EVD placement is safe, accurate, and cost effective in selective patients with hemorrhage-related hydrocephalus.

Objective To perform an individual patient–level data (IPLD) analysis and to determine the relationship between haptoglobin ( HP ) genotype and outcomes after aneurysmal subarachnoid hemorrhage (aSAH). Methods The primary outcome was favorable outcome on the modified Rankin Scale or Glasgow Outcome Scale up to 12 months after ictus. The secondary outcomes were occurrence of delayed ischemic neurologic deficit, radiologic infarction, angiographic vasospasm, and transcranial Doppler evidence of vasospasm. World Federation of Neurological Surgeons (WFNS) scale, Fisher grade, age, and aneurysmal treatment modality were covariates for both primary and secondary outcomes. As preplanned, a 2-stage IPLD analysis was conducted, followed by these sensitivity analyses: (1) unadjusted; (2) exclusion of unpublished studies; (3) all permutations of HP genotypes; (4) sliding dichotomy; (5) ordinal regression; (6) 1-stage analysis; (7) exclusion of studies not in Hardy-Weinberg equilibrium (HWE); (8) inclusion of studies without the essential covariates; (9) inclusion of additional covariates; and (10) including only covariates significant in univariate analysis. Results Eleven studies (5 published, 6 unpublished) totaling 939 patients were included. Overall, the study population was in HWE. Follow-up times were 1, 3, and 6 months for 355, 516, and 438 patients. HP genotype was not associated with any primary or secondary outcome. No trends were observed. When taken through the same analysis, higher age and WFNS scale were associated with an unfavorable outcome as expected. Conclusion This comprehensive IPLD analysis, carefully controlling for covariates, refutes previous studies showing that HP1-1 associates with better outcome after aSAH.

OBJECTIVEExternal ventricular drain (EVD) insertion is one of the most common emergency neurosurgical procedures. EVDs are traditionally inserted freehand (FH) in an emergency setting, but often result in suboptimal positioning. Image-guided surgery (IGS) is selectively used to assist placement. However, the accuracy and practicality of IGS use is yet to be reported. In this study, the authors set out to assess if IGS is practical and improves the accuracy of EVD placement.METHODSCase notes and images obtained in patients who underwent frontal EVD placement were retrospectively reviewed. Ventriculomegaly was determined by the measurement of the Evans index. EVD location was classified as optimal (ipsilateral frontal horn) or suboptimal (any other location). Propensity score matching of the two groups (IGS vs FH) for the Evans index was performed. Data were analyzed for patient age, diagnosis, number of EVDs, and complications. Those without postoperative CT scans were excluded.RESULTSA total of 607 patients with 760 EVDs placed were identified; 331 met inclusion criteria. Of these, 287 were inserted FH, and 44 were placed with IGS; 60.6% of all unmatched FH EVDs were optimal compared with 75% of the IGS group (p = 0.067). The IGS group had a significantly smaller Evans index (p < 0.0001). Propensity score matching demonstrated improved optimal position in the IGS group when compared with the matched FH group (75% vs 43.2%, OR 4.6 [1.5–14.6]; p = 0.002). Patients with an Evans index of ≥ 0.36 derived less benefit (75% in IGS vs 66% in FH, p = 0.5), and those with an Evans index < 0.36 derived more benefit (75% in IGS vs 53% in FH, p = 0.024). The overall EVD complication rate was 36% in the FH group versus 18% in the IGS group (p = 0.056). Revision rates were higher in the FH group (p = 0.035), and the operative times were similar (p = 0.69). Long intracranial EVD catheters were associated with tip malposition irrespective of the group.CONCLUSIONSImage guidance is practical and improves the accuracy of EVD placement in patients with small ventricles; thus, it should be considered for these patients.

Acute stroke due to supratentorial intracerebral haemorrhage is associated with high morbidity and mortality. Open craniotomy haematoma evacuation has not been found to have any benefit in large randomised trials. We assessed whether minimally invasive catheter evacuation followed by thrombolysis (MISTIE), with the aim of decreasing clot size to 15 mL or less, would improve functional outcome in patients with intracerebral haemorrhage. MISTIE III was an open-label, blinded endpoint, phase 3 trial done at 78 hospitals in the USA, Canada, Europe, Australia, and Asia. We enrolled patients aged 18 years or older with spontaneous, non-traumatic, supratentorial intracerebral haemorrhage of 30 mL or more. We used a computer-generated number sequence with a block size of four or six to centrally randomise patients to image-guided MISTIE treatment (1·0 mg alteplase every 8 h for up to nine doses) or standard medical care. Primary outcome was good functional outcome, defined as the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0-3 at 365 days, adjusted for group differences in prespecified baseline covariates (stability intracerebral haemorrhage size, age, Glasgow Coma Scale, stability intraventricular haemorrhage size, and clot location). Analysis of the primary efficacy outcome was done in the modified intention-to-treat (mITT) population, which included all eligible, randomly assigned patients who were exposed to treatment. All randomly assigned patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01827046. Between Dec 30, 2013, and Aug 15, 2017, 506 patients were randomly allocated: 255 (50%) to the MISTIE group and 251 (50%) to standard medical care. 499 patients (n=250 in the MISTIE group; n=249 in the standard medical care group) received treatment and were included in the mITT analysis set. The mITT primary adjusted efficacy analysis estimated that 45% of patients in the MISTIE group and 41% patients in the standard medical care group had achieved an mRS score of 0-3 at 365 days (adjusted risk difference 4% [95% CI -4 to 12]; p=0·33). Sensitivity analyses of 365-day mRS using generalised ordered logistic regression models adjusted for baseline variables showed that the estimated odds ratios comparing MISTIE with standard medical care for mRS scores higher than 5 versus 5 or less, higher than 4 versus 4 or less, higher than 3 versus 3 or less, and higher than 2 versus 2 or less were 0·60 (p=0·03), 0·84 (p=0·42), 0·87 (p=0·49), and 0·82 (p=0·44), respectively. At 7 days, two (1%) of 255 patients in the MISTIE group and ten (4%) of 251 patients in the standard medical care group had died (p=0·02) and at 30 days, 24 (9%) patients in the MISTIE group and 37 (15%) patients in the standard medical care group had died (p=0·07). The number of patients with symptomatic bleeding and brain bacterial infections was similar between the MISTIE and standard medical care groups (six [2%] of 255 patients vs three [1%] of 251 patients; p=0·33 for symptomatic bleeding; two [1%] of 255 patients vs 0 [0%] of 251 patients; p=0·16 for brain bacterial infections). At 30 days, 76 (30%) of 255 patients in the MISTIE group and 84 (33%) of 251 patients in the standard medical care group had one or more serious adverse event, and the difference in number of serious adverse events between the groups was statistically significant (p=0·012). For moderate to large intracerebral haemorrhage, MISTIE did not improve the proportion of patients who achieved a good response 365 days after intracerebral haemorrhage. The procedure was safely adopted by our sample of surgeons. National Institute of Neurological Disorders and Stroke and Genentech. [Abstract copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.]

We aim to describe the outcomes after chronic subdural hematoma drainage (CSDH) management in a large cohort of patients on antithrombotic drugs, either antiplatelets or anticoagulants, at presentation and to inform clinical decision making on the timing of surgery and recommencement of these drugs. We used data from a previous UK-based multi-center, prospective cohort study. Outcomes included recurrence within 60 days, functional outcome at discharge, and thromboembolic event during hospital stay. We performed Cox regression on recurrence and multiple logistic regression on functional outcome. There were 817 patients included in the analysis, of which 353 (43.2%) were on an antithrombotic drug at presentation. We observed a gradual reduction in risk of recurrence for patients during the 6 weeks post-CSDH surgery. Neither antiplatelet nor anticoagulant drug use influenced risk of CSDH recurrence (hazard ratio, 0.93; 95% confidence interval [CI], 0.58-1.48; p = 0.76) or persistent/worse functional impairment (odds ratio, 1.08; 95% CI, 0.76-1.55; p = 0.66). Delaying surgery after cessation of antiplatelet drug did not affect risk of bleed recurrence. There were 15 in-hospital thromboembolic events recorded. Events were more common in the group pre-treated with antithrombotic drugs (3.3%) compared to the non-antithrombotic group (0.9%). Patients on an antithrombotic drug pre-operatively were at higher risk of thromboembolic events with no excess risk of bleed recurrence or worse functional outcome after CSDH drainage. The data did not support delaying surgery in patients on antithrombotic therapy. In the absence of a randomized controlled trial, early surgery and early antithrombotic recommencement should be considered in those at high risk of thromboembolic events.

Background: Two randomised trials assessing the effectiveness of decompressive craniectomy (DC) following traumatic brain injury (TBI) were published in recent years: DECRA in 2011 and RESCUEicp in 2016. As the results have generated debate amongst clinicians and researchers working in the field of TBI worldwide, it was felt necessary to provide general guidance on the use of DC following TBI and identify areas of ongoing uncertainty via a consensus-based approach. Methods: The International Consensus Meeting on the Role of Decompressive Craniectomy in the Management of Traumatic Brain Injury took place in Cambridge, UK, on the 28th and 29th September 2017. The meeting was jointly organised by the World Federation of Neurosurgical Societies (WFNS), AO/Global Neuro and the NIHR Global Health Research Group on Neurotrauma. Discussions and voting were organised around six pre-specified themes: (1) primary DC for mass lesions, (2) secondary DC for intracranial hypertension, (3) peri-operative care, (4) surgical technique, (5) cranial reconstruction and (6) DC in low- and middle-income countries. Results: The invited participants discussed existing published evidence and proposed consensus statements. Statements required an agreement threshold of more than 70% by blinded voting for approval. Conclusions: In this manuscript, we present the final consensus-based recommendations. We have also identified areas of uncertainty, where further research is required, including the role of primary DC, the role of hinge craniotomy and the optimal timing and material for skull reconstruction. publishedVersion

Background Almost 30% of patients with subarachnoid hemorrhage (SAH) are found to have multiple aneurysms. This can potentially present a serious management dilemma when planning treatment. Magnetic resonance imaging vessel wall imaging (VWI) has been proposed as a reliable technique in differentiating between ruptured and unruptured aneurysms in patients with multiple intracranial aneurysms who present with SAH. Expert consensus now supports this as a possible use for the technique. Case Description Here we present a patient presenting a particular clinical dilemma with SAH and a left third nerve palsy and transient speech disturbance who had circumferential enhancement in the left larger 3.5-mm irregular middle cerebral artery aneurysm and no detectable enhancement in what was angiographically either a 1.5-mm smooth noncompressive left posterior communicating artery aneurysm or infundibulum, but was proved at surgery to be the culprit aneurysm. Conclusion Although a case of concurrent false positive and false negative in the same patient has not previously been reported, the positive predictive value of VWI for rupture status is known to be much lower than its negative predictive value, and a case like this might be expected to occur in 0.6% of patients. Therefore, whereas VWI is a valuable tool, it should be used in conjunction with, and not in lieu of, traditional indicators of aneurysm rupture.

The work presented in this paper is focused on the use of spectroscopy to identify the type of tissue of human brain samples employing support vector machine classifiers. Two different spectrometers were used to acquire infrared spectroscopic signatures in the wavenumber range between 1200⁻3500 cm−1. An extensive analysis was performed to find the optimal configuration for a support vector machine classifier and determine the most relevant regions of the spectra for this particular application. The results demonstrate that the developed algorithm is robust enough to classify the infrared spectroscopic data of human brain tissue at three different discrimination levels.

Objective. Evoked tympanic membrane displacement (TMD) measurements show a correlation with intracranial pressure (ICP). Attempts to use these measurements for non-invasive monitoring of ICP in patients have been limited by high measurement variability. Pulsing of the tympanic membrane at the cardiac frequency has been shown to be a significant source of the variability. In this study we describe a post processing method to remove the cardiac pulse waveform and assess the impact of this on the measurement and its repeatability. Approach. Three-hundred and sixteen healthy volunteers were recruited for evoked TMD measurements. The measurements were quantified by V m, defined as the mean displacement between the point of maximum inward displacement and the end of the stimulus. A sample of spontaneously pulsing TMDs was measured immediately before the evoked measurements. Simultaneous recording of the ECG allowed a heartbeat template to be extracted from the spontaneous data and subtracted from the evoked data. Intra-subject repeatability of V m was assessed from 20 repeats of the evoked measurement. Results with and without subtraction of the heartbeat template were compared. The difference was tested for significance using the Wilcoxon sign rank test. Main results. In left and right ears, both sitting and supine, application of the pulse correction significantly reduced the intra-subject variability of V m (p value range 4.0 × 10−27 to 2.0 × 10−31). The average improvement was from 98 ± 6 nl to 56 ± 4 nl. Significance. The pulse subtraction technique substantially improves the repeatability of evoked TMD measurements. This justifies further investigations to assess the use of TMD measurements in clinical applications where non-invasive tracking of changes in ICP would be useful.

The skull base is uniquely positioned to absorb force imparted to the craniofacial skeleton, thereby reducing brain injury. Less well understood is the effect of the direction of force imparted to the craniofacial skeleton on the severity of brain injury. Eighty-one patients from two UK major trauma centres who sustained a fronto-basal fracture were divided into two groups: those struck with predominantly anterior force and those by predominantly lateral force. The first recorded Glasgow Coma Score (GCS), requirement for intubation, and requirement for decompressive craniectomy were used as markers of the severity of brain injury. An average GCS of 5 was found in the lateral group and 14 in the anterior group; this difference was statistically significant (P

Although many disease models exist for neurodegenerative disease, the translation of basic research findings to clinic is very limited. Studies using freshly resected human brain tissue, commonly discarded from neurosurgical procedures, should complement on-going work using stem cell-derived human neurons and glia thus increasing the likelihood of success in clinical trials.Herein, the authors discuss key issues in the lack of translation from basic research to clinic. They also review the evidence that human neurons, both freshly resected brain tissue and stem cell-derived neurons, such as induced pluripotent stem cells (iPSCs), can be used for analysis of physiological and molecular mechanisms in health and disease. Furthermore, the authors compare and contrast studies using live human brain tissue and studies using induced human stem cell-derived neuron models. Using an example from the area of neurodegeneration, the authors suggest that replicating elements of research findings from animals and stem cell models in resected human brain tissue would strengthen our understanding of disease mechanisms and the therapeutic strategies and aid translation.The use of human brain tissue alongside iPSC-derived neural models can validate molecular mechanisms identified in rodent disease models and strengthen their relevance to humans. If drug target engagement and mechanism of cellular action can be validated in human brain tissue, this will increase the success rate in clinical research. The combined use of resected human brain tissue, alongside iPSC-derived neural models, could be considered a standard step in pre-clinical research and help to bridge the gap to clinical trials.

The use of primary human neural tissue for research provides an invaluable insight into human neural function that cannot be achieved in any other way. Despite this it is successfully collected and used in only a small minority of units. We have established a collaboration between the Wessex Neurological Centre and the University of Southampton that allows us to study using human tissue resected during neurosurgery, and have used this tissue for over a decade. Tissue is most commonly collected from oncological, epilepsy and vascular operations. Here we share our experiences of the practicalities of working with live human glioma tissue and try to provide some insights for practicing neuro-oncology surgeons. We discuss the ethical considerations and practical difficulties of the co-ordination of the clinical and academic teams, and challenge of optimization of the tissue for the research. We will present the mechanisms in place to optimize the study of human neural tissue. We will review the progression from resection of tissue from glioma surgery to epilepsy surgery to any neurosurgical procedure in which the normal brain is resected and tissue discarded. We discuss the different models that can be used and the application locally to glioma stem cells, pathways activated in TBI, tissue damage from haemoglobin, the electrophysiology of the normal brain and with age and the inflammatory response of microglia. We will present examples of the value of human tissue studies. Firstly we will show the importance of primary glioma tissue compared to established glioma cell lines. Secondly, we will demonstrate some electrophysiological differences between humans and rodent that could only be investigated through the use of live human tissue obtained at operation. We will also demonstrate how we have moved to streamline tissue collection and propose a move to establish a national framework for such experiments.

Objective: Although previous studies have shown associations between patient symptoms/outcomes and the spontaneous tympanic membrane displacement (spTMD) pulse amplitude, the contribution of the underlying intracranial pressure (ICP) signal to the spTMD pulse remains largely unknown. We have assessed the relative contributions of ICP and arterial blood pressure (ABP) on spTMD at different frequencies in order to determine whether spTMD contains information about the ICP above and beyond that contained in the ABP. Approach: Eleven patients, who all had invasive ICP and ABP measurements in situ, were recruited from our intensive care unit. Their spTMD was recorded and the power spectral densities of the three signals, as well as coherences between the signals, were calculated in the range 0.1–5 Hz. Simple and multiple coherences, coupled with statistical tests using surrogate data, were carried out to quantify the relative contributions of ABP and ICP to spTMD. Main results: Most power of the signals was found to predominate at respiration rate, heart rate, and their harmonics, with little outside of these frequencies. Analysis of the simple coherences found a slight preference for ICP transmission, beyond that from ABP, to the spTMD at lower frequencies (7/11 patients at respiration, 7/10 patients at respiration 1st harmonic) which is reversed at the higher frequencies (2/11 patients at heart rate and its 1st harmonic). Both ICP and ABP were found to independently contribute to the spTMD. The multiple coherence reinforced that ICP is preferentially being transmitted at respiration and respiration 1st harmonic. Significance: Both ABP and ICP contribute independently to the spTMD signal, with most power occurring at clear physiological frequencies—respiration and harmonics and heart rate and harmonics. There is information shared between the ICP and spTMD that is not present in ABP. This analysis has indicated that lower frequencies appear to favour ICP as the driver for spTMD.

Background The outcomes of microsurgery of previously coiled aneurysms have been poorly described, and little is known about the factors predictive of poor outcome. Here we aimed to identify predictors of poor outcome following microsurgery for previously coiled recurrent aneurysms. Methods In this retrospective cohort study of a prospectively maintained vascular database, we reviewed presentations, recurrent aneurysm measurements, surgery, and outcomes of microsurgical clipping of recurrent previously coiled intracranial aneurysms. Results Our series comprised 39 patients (mean age, 49 years; range, 22–70 years) who underwent microsurgical clipping of 40 previously coiled intracranial aneurysms. One patient suffered seizures, 1 patient experienced transient neurologic worsening, and 1 patient developed hyponatraemia, none of whom had long-term sequelae. Two patients sustained postoperative infarcts, for an overall incidence of permanent morbidity of 5.1%. There were no deaths or rebleeds on follow-up. In 3 patients, including the 2 patients with infarct and 1 patient with a transient deficit, an attempt was made to remove the coil ball. These patients had larger aneurysms (1106 mm3 vs. 135 mm3; P = 0.005), with larger coil balls (257 mm3 vs. 52 mm3; P = 0.01) and wider necks (7.09 mm vs. 2.69 mm; P = 0.02) but smaller remnant heights (1.59 mm vs. 1.99 mm; P = 0.04). They were also more likely to have prolapsing coil loops (3/3 vs. 3/27; P = 0.016). Conclusions Our study demonstrates good clinical outcomes from microsurgical clipping of recurrent aneurysms. In the vast majority of cases, clips can be applied primarily. Coil ball removal is associated with increased morbidity, and thus should be considered only as a second-line option, with the likely need identified before the initiation of surgery.

Hyperspectral imaging (HSI) allows for the acquisition of large numbers of spectral bands throughout the electromagnetic spectrum (within and beyond the visual range) with respect to the surface of scenes captured by sensors. Using this information and a set of complex classification algorithms, it is possible to determine which material or substance is located in each pixel. The work presented in this paper aims to exploit the characteristics of HSI to develop a demonstrator capable of delineating tumor tissue from brain tissue during neurosurgical operations. Improved delineation of tumor boundaries is expected to improve the results of surgery. The developed demonstrator is composed of two hyperspectral cameras covering a spectral range of 400-1700 nm. Furthermore, a hardware accelerator connected to a control unit is used to speed up the hyperspectral brain cancer detection algorithm to achieve processing during the time of surgery. A labeled dataset comprised of more than 300,000 spectral signatures is used as the training dataset for the supervised stage of the classification algorithm. In this preliminary study, thematic maps obtained from a validation database of seven hyperspectral images of in vivo brain tissue captured and processed during neurosurgical operations demonstrate that the system is able to discriminate between normal and tumor tissue in the brain. The results can be provided during the surgical procedure (~1 min), making it a practical system for neurosurgeons to use in the near future to improve excision and potentially improve patient outcomes.

OBJECTIVE Tympanic membrane displacements (TMDs) are used to non-invasively gauge inner-ear fluid pressure. Inner-ear fluid pressure equalizes with intracranial pressure (ICP) via the cochlear aqueduct and therefore TMDs can indirectly evaluate ICP. We studied the relationship between two TMD modalities, evoked and spontaneous. Evoked TMD is a reflex response to an auditory stimulus and the established stapes-footplate mechanism explains how evoked TMDs change with ICP. Spontaneous TMD refers to a pulsatile TMD waveform expressed in the form of pulse amplitudes (TMD-PAs), the origins of which are poorly understood. We investigated whether both modalities respond similarly to an ICP change, suggesting a common mechanism. APPROACH ICP was manipulated in 20 healthy volunteers by a postural change from sitting (lower ICP) to supine (higher ICP). Differences between paired sitting and supine TMD results generated ΔEvoked and ΔSpontaneous values. MAIN RESULTS Evoked TMDs became more inward on lying supine while spontaneous TMDs became more outward. There was no evidence of a correlation between ΔEvoked and ΔSpontaneous (Right ears: r = -0.38, p = 0.10, 95% CI -0.75 to 0.21; Left ears: r = 0.34, p = 0.16, 95% CI -0.17 to 0.75). SIGNIFICANCE This suggests the stapes-footplate mechanism is not the primary mechanism explaining how spontaneous TMDs respond to changing ICP.

Abnormalities in Matrix Metalloproteinase (MMP) genes, which are important in extracellular matrix (ECM) maintenance and therefore arterial wall integrity are a plausible underlying mechanism of intracranial aneurysm (IA) formation, growth and subsequent rupture. We investigated whether the rs243865 C T SNP (single nucleotide polymorphism) within the MMP-2 gene (which influences gene transcription) is associated with IA compared to matched controls.We conducted a case-control genetic association study, adjusted for known IA risk factors (smoking and hypertension), in a UK Caucasian population of 1409 patients with intracranial aneurysms (IA), and 1290 matched controls, to determine the association of the rs243865 C T functional MMP-2 gene SNP with IA (overall, and classified as ruptured and unruptured). We also undertook a meta-analysis of two previous studies examining this SNP.The rs243865 T allele was associated with IA presence in univariate (OR 1.18 [95% CI 1.04-1.33], p = .01) and in multi-variable analyses adjusted for smoking and hypertension status (OR 1.16 [95% CI 1.01-1.35], p = .042). Subgroup analysis demonstrated an association of the rs243865 SNP with ruptured IA (OR 1.18 [95% CI 1.03-1.34] p = .017), but, not unruptured IA (OR 1.17 [95% CI 0.97-1.42], p = .11).Our study demonstrated an association between the functional MMP-2 rs243865 variant and IAs. Our findings suggest a genetic role for altered extracellular matrix integrity in the pathogenesis of IA development and rupture.

Increasing age and lower pre-operative Glasgow coma score (GCS) are associated with worse outcome after surgery for chronic subdural haematoma (CSDH). Only few studies have quantified outcomes specific to the very elderly or comatose patients. We aim to examine surgical outcomes in these patient groups. We analysed data from a prospective multicentre cohort study, assessing the risk of recurrence, death, and unfavourable functional outcome of very elderly (≥ 90 years) patients and comatose (pre-operative GCS ≤ 8) patients following surgical treatment of CSDH. Seven hundred eighty-five patients were included in the study. Thirty-two (4.1%) patients had pre-operative GCS ≤ 8 and 70 (8.9%) patients were aged ≥ 90 years. A higher proportion of comatose patients had an unfavourable functional outcome (38.7 vs 21.7%; p = 0.03), although similar proportion of comatose (64.5%) and non-comatose patients (61.8%) functionally improved after surgery (p = 0.96). Compared to patients aged

Objectives: Evoked tympanic membrane displacement (TMD) measurements, quantified by Vm, record small volume changes in the ear canal following stimulation of the acoustic reflex. Vm shows a correlation with intracranial pressure (ICP) and has been proposed as an option to non-invasively measure ICP. The spontaneous pulsing of the tympanic membrane, driven by the cardiovascular pulse, may contaminate the recordings and contribute to high measurement variability in some subjects. This study hypothesised that the larger the spontaneous vascular pulse, the larger the variability in Vm.

Functional outcome after subarachnoid haemorrhage has traditionally been assessed using scales developed for other neurological conditions. The modified Rankin score and Glasgow Outcome Scale are most commonly used. Employment of these scales in subarachnoid haemorrhage is hampered by well recognized limitations. We set out to develop and validate a new condition-specific subarachnoid haemorrhage outcome tool (SAHOT). Items addressing diverse aspects of the impact of subarachnoid haemorrhage were collected during focus groups involving patients, next-of-kin and multidisciplinary professionals involved in subarachnoid haemorrhage management. After a series of iterative revisions, the resultant questionnaire was applied to patients and their next-of-kin at 1, 3 and 6 months post-subarachnoid haemorrhage. Rasch methodology was used to finalize the structure of the questionnaire and explore the extent to which SAHOT scores met Rasch-based criteria of successful measurement. The SAHOT was further assessed using traditional scale evaluation techniques, and validated in a second separate subarachnoid haemorrhage patient cohort. The final SAHOT included 56 items dealing with cognitive, physical, and behavioural/psychological consequences of subarachnoid haemorrhage. Rasch analysis indicated the scale successfully measured functional outcome post-subarachnoid haemorrhage. Three item scoring categories produced the best scale performance. There was no evidence of differential item functioning between patients and next-of-kin. The SAHOT was found to be acceptable, have good convergent and divergent validity, good discrimination and excellent responsiveness. It was successfully validated in a second subarachnoid haemorrhage patient cohort. The SAHOT offers the first subarachnoid haemorrhage-specific scientifically robust outcome measure with potential utility in neurovascular clinical services and research studies.