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Due to the risk of intracranial aneurysm (IA) recurrence and the potential requirement for re-treatment following endovascular treatment (EVT), radiological follow-up of these aneurysms is necessary. There is little evidence to guide the duration and frequency of this follow-up. The aim of this study was to establish the current practice in neurosurgical units in the UK and Ireland.A survey was designed with input from interventional neuroradiologists and neurosurgeons. Neurovascular consultants in each of the 30 neurosurgical units providing a neurovascular service in the UK and Ireland were contacted and asked to respond to questions regarding the follow-up practice for IA treated with EVT in their department.Responses were obtained from 28/30 (94%) of departments. There was evidence of wide variations in the duration and frequency of follow-up, with a minimum follow-up duration for ruptured IA that varied from 18 months in 5/28 (18%) units to 5 years in 11/28 (39%) of units. Young patient age, previous subarachnoid haemorrhage and incomplete IA occlusion were cited as factors that would prompt more intensive surveillance, although larger and broad-necked IA were not followed-up more closely in the majority of departments.There is a wide variation in the radiological follow-up of IA treated with EVT in the UK and Ireland. Further standardisation of this aspect of patient care is likely to be beneficial, but further evidence on the behaviour of IA following EVT is required in order to inform this process.

Background and purposeNuclear factor erythroid 2-related factor 2 (NRF2; encoded by the NFE2L2 gene) has been implicated in outcome following aneurysmal subarachnoid haemorrhage (aSAH) through its activity as a regulator of inflammation, oxidative injury and blood breakdown product clearance. The aim of this study was to identify whether genetic variation in NFE2L2 is associated with clinical outcome following aSAH.MethodsTen tagging single nucleotide polymorphisms (SNPs) in NFE2L2 were genotyped and tested for association with dichotomized clinical outcome, assessed by the modified Rankin scale, in both a discovery and a validation cohort. In silico functional analysis was performed using a range of bioinformatic tools.ResultsOne SNP, rs10183914, was significantly associated with outcome following aSAH in both the discovery (n = 1007) and validation cohorts (n = 466). The risk of poor outcome was estimated to be 1.33-fold (95% confidence interval 1.12–1.58) higher in individuals with the T allele of rs10183914 (pmeta-analysis = 0.001). In silico functional analysis identified rs10183914 as a potentially regulatory variant with effects on transcription factor binding in addition to alternative splicing with the T allele, associated with a significant reduction in the NFE2L2 intron excision ratio (psQTL = 1.3 × 10−7).ConclusionsThe NFE2L2 SNP, rs10183914, is significantly associated with outcome following aSAH. This is consistent with a clinically relevant pathophysiological role for oxidative and inflammatory brain injury due to blood and its breakdown products in aSAH. Furthermore, our findings support NRF2 as a potential therapeutic target following aSAH and other forms of intracranial haemorrhage.

BACKGROUND Traumatic acute subdural hematomas frequently warrant surgical evacuation by means of a craniotomy (bone flap replaced) or decompressive craniectomy (bone flap not replaced). Craniectomy may prevent intracranial hypertension, but whether it is associated with better outcomes is unclear. METHODS We conducted a trial in which patients undergoing surgery for traumatic acute subdural hematoma were randomly assigned to undergo craniotomy or decompressive craniectomy. An inclusion criterion was a bone flap with an anteroposterior diameter of 11 cm or more. The primary outcome was the rating on the Extended Glasgow Outcome Scale (GOSE) (an 8-point scale, ranging from death to "upper good recovery" [no injury-related problems]) at 12 months. Secondary outcomes included the GOSE rating at 6 months and quality of life as assessed by the EuroQol Group 5-Dimension 5-Level questionnaire (EQ-5D-5L). RESULTS A total of 228 patients were assigned to the craniotomy group and 222 to the decompressive craniectomy group. The median diameter of the bone flap was 13 cm (interquartile range, 12 to 14) in both groups. The common odds ratio for the differences across GOSE ratings at 12 months was 0.85 (95% confidence interval, 0.60 to 1.18; P = 0.32). Results were similar at 6 months. At 12 months, death had occurred in 30.2% of the patients in the craniotomy group and in 32.2% of those in the craniectomy group; a vegetative state occurred in 2.3% and 2.8%, respectively, and a lower or upper good recovery occurred in 25.6% and 19.9%. EQ-5D-5L scores were similar in the two groups at 12 months. Additional cranial surgery within 2 weeks after randomization was performed in 14.6% of the craniotomy group and in 6.9% of the craniectomy group. Wound complications occurred in 3.9% of the craniotomy group and in 12.2% of the craniectomy group. CONCLUSIONS Among patients with traumatic acute subdural hematoma who underwent craniotomy or decompressive craniectomy, disability and quality-of-life outcomes were similar with the two approaches. Additional surgery was performed in a higher proportion of the craniotomy group, but more wound complications occurred in the craniectomy group. (Funded by the National Institute for Health and Care Research; RESCUE-ASDH ISRCTN Registry number, ISRCTN87370545.)

OBJECTIVE There is a reported elevated risk of cerebral aneurysms in patients with intracranial dural arteriovenous fistulas (dAVFs). However, the natural history, rate of spontaneous regression, and ideal treatment regimen are not well characterized. In this study, the authors aimed to describe the characteristics of patients with dAVFs and intracranial aneurysms and propose a classification system. METHODS The Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR) database from 12 centers was retrospectively reviewed. Analysis was performed to compare dAVF patients with (dAVF+ cohort) and without (dAVF-only cohort) concomitant aneurysm. Aneurysms were categorized based on location as a dAVF flow-related aneurysm (FRA) or a dAVF non–flow-related aneurysm (NFRA), with further classification as extra- or intradural. Patients with traumatic pseudoaneurysms or aneurysms with associated arteriovenous malformations were excluded from the analysis. Patient demographics, dAVF anatomical information, aneurysm information, and follow-up data were collected. RESULTS Of the 1077 patients, 1043 were eligible for inclusion, comprising 978 (93.8%) and 65 (6.2%) in the dAVF-only and dAVF+ cohorts, respectively. There were 96 aneurysms in the dAVF+ cohort; 10 patients (1%) harbored 12 FRAs, and 55 patients (5.3%) harbored 84 NFRAs. Dural AVF+ patients had higher rates of smoking (59.3% vs 35.2%, p < 0.001) and illicit drug use (5.8% vs 1.5%, p = 0.02). Sixteen dAVF+ patients (24.6%) presented with aneurysm rupture, which represented 16.7% of the total aneurysms. One patient (1.5%) had aneurysm rupture during follow-up. Patients with dAVF+ were more likely to have a dAVF located in nonconventional locations, less likely to have arterial supply to the dAVF from external carotid artery branches, and more likely to have supply from pial branches. Rates of cortical venous drainage and Borden type distributions were comparable between cohorts. A minority (12.5%) of aneurysms were FRAs. The majority of the aneurysms underwent treatment via either endovascular (36.5%) or microsurgical (15.6%) technique. A small proportion of aneurysms managed conservatively either with or without dAVF treatment spontaneously regressed (6.2%). CONCLUSIONS Patients with dAVF have a similar risk of harboring a concomitant intracranial aneurysm unrelated to the dAVF (5.3%) compared with the general population (approximately 2%–5%) and a rare risk (0.9%) of harboring an FRA. Only 50% of FRAs are intradural. Dural AVF+ patients have differences in dAVF angioarchitecture. A subset of dAVF+ patients harbor FRAs that may regress after dAVF treatment.

Sphingosine-1-phosphate (S1P) is generated intracellularly and, when transported to the extracellular compartment, predominantly signals through S1P receptors. The S1P signalling pathway has been implicated in the pathophysiology of neurological injury following aneurysmal subarachnoid haemorrhage (aSAH). In this review, we bring together all the available data regarding the role of S1P in neurological injury following aSAH. There is agreement in the literature that S1P increases in the cerebrospinal fluid following aSAH and leads to cerebral artery vasospasm. On the other hand, the role of S1P in the parenchyma is less clear cut, with different studies arguing for beneficial and deleterious effects. A parsimonious interpretation of this apparently conflicting data is presented. We discuss the potential of S1P receptor modulators, in clinical use for multiple sclerosis, to be repurposed for aSAH. Finally, we highlight the gaps in our knowledge of S1P signalling in humans, the clinical challenges of targeting the S1P pathway after aSAH and other research priorities.

During subarachnoid haemorrhage, a blood clot forms in the subarachnoid space releasing extracellular haemoglobin (Hb), which causes oxidative damage and cell death in surrounding tissues. High rates of disability and cognitive decline in SAH survivors is attributed to loss of neurons and functional connections during secondary brain injury. Haptoglobin sequesters Hb for clearance, but this scavenging system is overwhelmed after a haemorrhage. Whilst exogenous haptoglobin application can attenuate cytotoxicity of Hb andin vivo, andin vivothe functional effects of sub-lethal Hb concentrations on surviving neurons and whether cellular function can be protected with haptoglobin treatment remain unclear. Here we use cultured neurons to investigate neuronal health and function across a range of Hb concentrations to establish the thresholds for cellular damage and investigate synaptic function. Hb impairs ATP concentrations and cytoskeletal structure. At clinically relevant but sublethal Hb concentrations, synaptic AMPAR-driven currents are reduced, accompanied by a reduction in GluA1 subunit expression. Haptoglobin co-application can prevent these deficits by scavenging free Hb to reduce it to sub-threshold concentrations and does not need to be present at stoichiometric amounts to achieve efficacy. Haptoglobin itself does not impair measures of neuronal health and function at any concentration tested. Our data highlight a role for Hb in modifying synaptic function after SAH, which may link to impaired cognition or plasticity, and support the development of haptoglobin as a therapy for subarachnoid haemorrhage.

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating form of stroke frequently affecting young to middle-aged adults, with an unmet need to improve outcome. This special report focusses on the development of intrathecal haptoglobin supplementation as a treatment by reviewing current knowledge and progress, arriving at a Delphi-based global consensus regarding the pathophysiological role of extracellular hemoglobin and research priorities for clinical translation of hemoglobin-scavenging therapeutics. After aneurysmal subarachnoid hemorrhage, erythrocyte lysis generates cell-free hemoglobin in the cerebrospinal fluid, which is a strong determinant of secondary brain injury and long-term clinical outcome. Haptoglobin is the body’s first-line defense against cell-free hemoglobin by binding it irreversibly, preventing translocation of hemoglobin into the brain parenchyma and nitric oxide-sensitive functional compartments of cerebral arteries. In mouse and sheep models, intraventricular administration of haptoglobin reversed hemoglobin-induced clinical, histological, and biochemical features of human aneurysmal subarachnoid hemorrhage. Clinical translation of this strategy imposes unique challenges set by the novel mode of action and the anticipated need for intrathecal drug administration, necessitating early input from stakeholders. Practising clinicians (n=72) and scientific experts (n=28) from 5 continents participated in the Delphi study. Inflammation, microvascular spasm, initial intracranial pressure increase, and disruption of nitric oxide signaling were deemed the most important pathophysiological pathways determining outcome. Cell-free hemoglobin was thought to play an important role mostly in pathways related to iron toxicity, oxidative stress, nitric oxide, and inflammation. While useful, there was consensus that further preclinical work was not a priority, with most believing the field was ready for an early phase trial. The highest research priorities were related to confirming haptoglobin’s anticipated safety, individualized versus standard dosing, timing of treatment, pharmacokinetics, pharmacodynamics, and outcome measure selection. These results highlight the need for early phase trials of intracranial haptoglobin for aneurysmal subarachnoid hemorrhage, and the value of early input from clinical disciplines on a global scale during the early stages of clinical translation.

Objective Unruptured intracranial aneurysms (UIA) are common. For many the treatment risks outweigh their risk of subarachnoid haemorrhage and patients undergo surveillance imaging. There is little data to inform if and how to monitor UIAs resulting in widely varying practices. This study aimed to determine the current practice of unruptured UIA surveillance in the United Kingdom. Methods A questionnaire was designed to address the themes of surveillance protocols for UIA including when surveillance is initiated, how frequently it is performed, and when it is terminated. Additionally, how aneurysm growth is managed and how clinically meaningful growth is defined were explored. The questionnaire was distributed to members of the British Neurovascular Group using probability-based cluster and non-probability purposive sampling methods. Results Responses were received from 30 of the 30 (100.0%) adult neurosurgical units in the United Kingdom of which 27 (90.0%) routinely perform surveillance for aneurysm growth. Only four units had a unit policy. The mean patient age up to which a unit would initiate follow-up of a low-risk UIA was 65.4 ± 9.0 years. The time points at which imaging is performed varied widely. There was an even split between whether units use a fixed duration of follow-up or an age threshold for terminating surveillance. Forty percent of units will follow-up patients more than 5 years from diagnosis. The magnitude in the change in size that was felt to constitute growth ranged from 1 to 3mm. No units routinely used vessel wall imaging although 27 had access to 3T MRI capable of performing it. Conclusions There is marked heterogeneity in surveillance practices between units in the United Kingdom. This study will help units better understand their practice relative to their peers and provide a framework forplanning further research on aneurysm growth.

Objective: to assess the long-term frequency, prognosis, and phenotype of persistent headache following aneurysmal subarachnoid hemorrhage (aSAH).Background: very little is known about long-term headache following aSAH with no studies looking beyond 3 years.Methods: retrospective analysis comparing aSAH cases to matched controls in the UK Biobank, a prospective cohort study. Headache frequency and phenotype were compared using group comparison tests. The relationship between headache fre-quency and time was assessed using correlation analysis.Results: headache was more frequent following aSAH (aSAH: 258/864 [29.9%] vs. controls: 666/3456 [19.3%], χ2= 45.5, p< 0.001) at a median follow-up of 7.5 years. Headache frequency decreased over time (RS= −0.71, p= 0.028), affecting 29/58 (50%) patients in the first year and reducing to 13/47 (28%) patients 10 years later. Headache frequency was not related to aSAH severity (z= 0.249, p= 0.803), treat-ment (z= 0.583, p= 0.560), or hydrocephalus (z= −1.244, p= 0.214). There was a consistently higher frequency of migrainous features following aSAH compared to controls, although this did not reach statistical significance.Conclusions: persistent headache is more frequent following aSAH compared to con-trols in the long term and the prevalence reduces gradually over time. The increased frequency of migrainous features suggests that selected patients with post-aSAH headache may benefit from migraine treatment.

Background and purposeFatigue is common following aneurysmal subarachnoid haemorrhage (aSAH) but little is known about its frequency, prognosis and impact on employment. The aim of this study was to assess the frequency of fatigue, whether it changes over time and the relationship to employment in the long term.MethodsThis was a retrospective observational study of aSAH cases and matched controls from the UK Biobank. The presence of fatigue was compared between cases and controls using the chi-squared test. The change in frequency over time was assessed using Spearman's rank correlation coefficient. The effect of fatigue on employment was assessed using mediation analysis.ResultsFatigue is more common following aSAH compared to matched controls (aSAH 18.7%; controls 13.7%; χ2 = 13.0, p ConclusionsFatigue is common following aSAH and persists in the long term. It gradually improves over time but has a major impact on aSAH survivors, significantly contributing to unemployment following haemorrhage. Further work is required to develop treatments and management strategies for fatigue with a view to improving this symptom and consequently employment following aSAH.

Previous studies investigating the relationship between aspirin use and subarachnoid haemorrhage (SAH) have yielded conflicting results. In this study, we aimed to clarify the association between aspirin and SAH in the general population. The UK Biobank is a prospective population-based cohort study. Sex, age, smoking, alcohol, medication use, hypertension, blood pressure, ischaemic heart disease and stroke were recorded at baseline assessments. Follow-up is conducted through linkages to National Health Service data including electronic, coded death certificate, hospital and primary care data. Cox proportional hazards modelling was used to analyse the association between aspirin use and SAH. Of the 501,060 participants included in the analysis, a total of 579 suffered from spontaneous SAH after their baseline assessment. There was no relationship between aspirin and SAH of all causes (HR, 1.16 [0.92-1.46]), aneurysmal SAH (HR, 1.15 [0.91-1.47]) or non-aneurysmal SAH (HR, 1.29 [0.54-3.09]). Aspirin use was associated with SAH resulting in death (HR, 1.69 [1.14-2.51]), especially out of hospital death (HR, 2.10 [1.13-3.91]). Despite reports of a protective association between aspirin and SAH in patients with known unruptured aneurysms, this study has not demonstrated the same effect in the general population. However, aspirin users were more likely to suffer SAH resulting in death, especially out of hospital.

BackgroundTools predicting intracranial dural arteriovenous fistulas (dAVFs) treatment outcomes remain scarce. This study aimed to use a multicenter database comprising more than 1000 dAVFs to develop a practical scoring system that predicts treatment outcomes.MethodsPatients with angiographically confirmed dAVFs who underwent treatment within the Consortium for Dural Arteriovenous Fistula Outcomes Research-participating institutions were retrospectively reviewed. A subset comprising 80% of patients was randomly selected as training dataset, and the remaining 20% was used for validation. Univariable predictors of complete dAVF obliteration were entered into a stepwise multivariable regression model. The components of the proposed score (VEBAS) were weighted based on their ORs. Model performance was assessed using receiver operating curves (ROC) and areas under the ROC.ResultsA total of 880 dAVF patients were included. Venous stenosis (presence vs absence), elderly age (ConclusionThe VEBAS score is a practical grading system that can guide patient counseling when considering dAVF intervention by predicting the likelihood of treatment success, with higher scores portending a greater likelihood of complete obliteration.

OBJECTIVE Cranial dural arteriovenous fistulas (dAVFs) are often treated with endovascular therapy, but occasionally a multimodality approach including surgery and/or radiosurgery is utilized. Recurrence after an initial angiographic cure has been reported, with estimated rates ranging from 2% to 14.3%, but few risk factors have been identified. The objective of this study was to identify risk factors associated with recurrence of dAVF after putative cure. METHODS The Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR) data were retrospectively reviewed. All patients with angiographic cure after treatment and subsequent angiographic follow-up were included. The primary outcome was recurrence, with risk factor analysis. Secondary outcomes included clinical outcomes, morbidity, and mortality associated with recurrence. Risk factor analysis was performed comparing the group of patients who experienced recurrence with those with durable cure (regardless of multiple recurrences). Time-to-event analysis was performed using all collective recurrence events (multiple per patients in some cases). RESULTS Of the 1077 patients included in the primary CONDOR data set, 457 met inclusion criteria. A total of 32 patients (7%) experienced 34 events of recurrence at a mean of 368.7 days (median 192 days). The recurrence rate was 4.5% overall. Kaplan-Meier analysis predicted long-term recurrence rates approaching 11% at 3 years. Grade III dAVFs treated with endovascular therapy were statistically significantly more likely to experience recurrence than those treated surgically (13.3% vs 0%, p = 0.0001). Tentorial location, cortical venous drainage, and deep cerebral venous drainage were all risk factors for recurrence. Endovascular intervention and radiosurgery were associated with recurrence. Six recurrences were symptomatic, including 2 with hemorrhage, 3 with nonhemorrhagic neurological deficit, and 1 with progressive flow-related symptoms (decreased vision). CONCLUSIONS Recurrence of dAVFs after putative cure can occur after endovascular treatment. Risk factors include tentorial location, cortical venous drainage, and deep cerebral drainage. Multimodality therapy can be used to achieve cure after recurrence. A delayed long-term angiographic evaluation (at least 1 year from cure) may be warranted, especially in cases with risk factors for recurrence.

OBJECTIVE Cranial dural arteriovenous fistulas (dAVFs) are rare lesions, hampering efforts to understand them and improve their care. To address this challenge, investigators with an established record of dAVF investigation formed an international, multicenter consortium aimed at better elucidating dAVF pathophysiology, imaging characteristics, natural history, and patient outcomes. This report describes the design of the Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR) and includes characterization of the 1077-patient cohort. METHODS Potential collaborators with established interest in the field were identified via systematic review of the literature. To ensure uniformity of data collection, a quality control process was instituted. Data were retrospectively obtained. RESULTS CONDOR comprises 14 centers in the United States, the United Kingdom, the Netherlands, and Japan that have pooled their data from 1077 dAVF patients seen between 1990 and 2017. The cohort includes 359 patients (33%) with Borden type I dAVFs, 175 (16%) with Borden type II fistulas, and 529 (49%) with Borden type III fistulas. Overall, 852 patients (79%) presented with fistula-related symptoms: 427 (40%) presented with nonaggressive symptoms such as tinnitus or orbital phenomena, 258 (24%) presented with intracranial hemorrhage, and 167 (16%) presented with nonhemorrhagic neurological deficits. A smaller proportion (224 patients, 21%), whose dAVFs were discovered incidentally, were asymptomatic. Many patients (85%, 911/1077) underwent treatment via endovascular embolization (55%, 587/1077), surgery (10%, 103/1077), radiosurgery (3%, 36/1077), or multimodal therapy (17%, 184/1077). The overall angiographic cure rate was 83% (758/911 treated), and treatment-related permanent neurological morbidity was 2% (27/1467 total procedures). The median time from diagnosis to follow-up was 380 days (IQR 120–1038.5 days). CONCLUSIONS With more than 1000 patients, the CONDOR registry represents the largest registry of cranial dAVF patient data in the world. These unique, well-annotated data will enable multiple future analyses to be performed to better understand dAVFs and their management.

OBJECTIVE Current evidence suggests that intracranial dural arteriovenous fistulas (dAVFs) without cortical venous drainage (CVD) have a benign clinical course. However, no large study has evaluated the safety and efficacy of current treatments and their impact over the natural history of dAVFs without CVD. METHODS The authors conducted an analysis of the retrospectively collected multicenter Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR) database. Patient demographics and presenting symptoms, angiographic features of the dAVFs, and treatment outcomes of patients with Borden type I dAVFs were reviewed. Clinical and radiological follow-up information was assessed to determine rates of new intracranial hemorrhage (ICH) or nonhemorrhagic neurological deficit (NHND), worsening of venous hyperdynamic symptoms (VHSs), angiographic recurrence, and progression or spontaneous regression of dAVFs over time. RESULTS A total of 342 patients/Borden type I dAVFs were identified. The mean patient age was 58.1 ± 15.6 years, and 62% were women. The mean follow-up time was 37.7 ± 54.3 months. Of 230 (67.3%) treated dAVFs, 178 (77%) underwent mainly endovascular embolization, 11 (4.7%) radiosurgery alone, and 4 (1.7%) open surgery as the primary modality. After the first embolization, most dAVFs (47.2%) achieved only partial reduction in early venous filling. Multiple complementary interventions increased complete obliteration rates from 37.9% after first embolization to 46.7% after two or more embolizations, and 55.2% after combined radiosurgery and open surgery. Immediate postprocedural complications occurred in 35 dAVFs (15.2%) and 6 (2.6%) with permanent sequelae. Of 127 completely obliterated dAVFs by any therapeutic modality, 2 (1.6%) showed angiographic recurrence/recanalization at a mean of 34.2 months after treatment. Progression to Borden-Shucart type II or III was documented in 2.2% of patients and subsequent development of a new dAVF in 1.6%. Partial spontaneous regression was found in 22 (21.4%) of 103 nontreated dAVFs. Multivariate Cox regression analysis demonstrated that older age, NHND, or severe venous-hyperdynamic symptoms at presentation and infratentorial location were associated with worse prognosis. Kaplan-Meier curves showed no significant difference for stable/improved symptoms survival probability in treated versus nontreated dAVFs. However, estimated survival times showed better trends for treated dAVFs compared with nontreated dAVFs (288.1 months vs 151.1 months, log-rank p = 0.28). This difference was statistically significant for treated dAVFs with 100% occlusion (394 months, log-rank p < 0.001). CONCLUSIONS Current therapeutic modalities for management of dAVFs without CVD may provide better symptom control when complete angiographic occlusion is achieved.

Objectives Masson tumor or intravascular papillary endothelial cell proliferation was first described in 1923. Only a few cases of intracranial Masson tumor have been reported following stereotactic radiosurgery (SRS). We report a series of 6 cases, age range 28–56 years, with intracranial Masson tumor following SRS for treatment of an intracranial arteriovenous malformation (AVM). Methods We performed a retrospective case note review, reviewed the imaging, SRS records, and neuropathology specimens following surgical excision. Results In our series all patients received Leksell SRS with the periphery of the AVM receiving doses ranging from 22–25 Gy. The time lapse from SRS to a clear enhancing mass appearing on imaging ranged from 5–10 years. Four patients underwent craniotomy and excision of the enhancing lesion for persistent edema and an enlarging cyst resulting in a resolution of symptoms. Conclusions SRS is an effective treatment for obliteration of intracranial AVMs.

Background Long-term outcome after subarachnoid hemorrhage, beyond the first few months, is difficult to predict, but has critical relevance to patients, their families, and carers. Objective To assess the performance of the Subarachnoid Hemorrhage International Trialists (SAHIT) prediction models, which were initially designed to predict short-term (90 d) outcome, as predictors of long-term (2 yr) functional outcome after aneurysmal subarachnoid hemorrhage (aSAH). Methods We included 1545 patients with angiographically-proven aSAH from the Genetic and Observational Subarachnoid Haemorrhage (GOSH) study recruited at 22 hospitals between 2011 and 2014. We collected data on age, WNFS grade on admission, history of hypertension, Fisher grade, aneurysm size and location, as well as treatment modality. Functional outcome was measured by the Glasgow Outcome Scale (GOS) with GOS 1 to 3 corresponding to unfavorable and 4 to 5 to favorable functional outcome, according to the SAHIT models. The SAHIT models were assessed for long-term outcome prediction by estimating measures of calibration (calibration slope) and discrimination (area under the receiver-operating characteristic curve [AUC]) in relation to poor clinical outcome. Results Follow-up was standardized to 2 yr using imputation methods. All 3 SAHIT models demonstrated acceptable predictive performance for long-term functional outcome. The estimated AUC was 0.71 (95% CI: 0.65-0.76), 0.73 (95% CI: 0.68-0.77), and 0.74 (95% CI: 0.69-0.79) for the core, neuroimaging, and full models, respectively; the calibration slopes were 0.86, 0.84, and 0.89, indicating good calibration. Conclusion The SAHIT prediction models, incorporating simple factors available on hospital admission, show good predictive performance for long-term functional outcome after aSAH.

BackgroundHuman neural stem cell implantation may offer improved recovery from stroke. We investigated the feasibility of intracerebral implantation of the allogeneic human neural stem cell line CTX0E03 in the subacute—chronic recovery phase of stroke and potential measures of therapeutic response in a multicentre study.MethodsWe undertook a prospective, multicentre, single-arm, open-label study in adults aged >40 years with significant upper limb motor deficits 2–13 months after ischaemic stroke. 20 million cells were implanted by stereotaxic injection to the putamen ipsilateral to the cerebral infarct. The primary outcome was improvement by 2 or more points on the Action Research Arm Test (ARAT) subtest 2 at 3 months after implantation.FindingsTwenty-three patients underwent cell implantation at eight UK hospitals a median of 7 months after stroke. One of 23 participants improved by the prespecified ARAT subtest level at 3 months, and three participants at 6 and 12 months. Improvement in ARAT was seen only in those with residual upper limb movement at baseline. Transient procedural adverse effects were seen, but no cell-related adverse events occurred up to 12 months of follow-up. Two deaths were unrelated to trial procedures.InterpretationAdministration of human neural stem cells by intracerebral implantation is feasible in a multicentre study. Improvements in upper limb function occurred at 3, 6 and 12 months, but not in those with absent upper limb movement at baseline, suggesting a possible target population for future controlled trials.FundingReNeuron, Innovate UK (application no 32074-222145).Trial registration numberEudraCT Number: 2012-003482-18

ObjectiveAfter aneurysmal subarachnoid haemorrhage (aSAH), extracellular haemoglobin (Hb) in the subarachnoid space is bound by haptoglobin, neutralising Hb toxicity and helping its clearance. Two exons in the HP gene (encoding haptoglobin) exhibit copy number variation (CNV), giving rise to HP1 and HP2 alleles, which influence haptoglobin expression level and possibly haptoglobin function. We hypothesised that the HP CNV associates with long-term outcome beyond the first year after aSAH.MethodsThe HP CNV was typed using quantitative PCR in 1299 aSAH survivors in the Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study, a retrospective multicentre cohort study with a median follow-up of 18 months. To investigate mediation of the HP CNV effect by haptoglobin expression level, as opposed to functional differences, we used rs2000999, a single nucleotide polymorphism associated with haptoglobin expression independent of the HP CNV. Outcome was assessed using modified Rankin and Glasgow Outcome Scores. SAH volume was dichotomised on the Fisher grade. Haemoglobin-haptoglobin complexes were measured in cerebrospinal fluid (CSF) of 44 patients with aSAH and related to the HP CNV.ResultsThe HP2 allele associated with a favourable long-term outcome after high-volume but not low-volume aSAH (multivariable logistic regression). However rs2000999 did not predict outcome. The HP2 allele associated with lower CSF haemoglobin-haptoglobin complex levels. The CSF Hb concentration after high-volume and low-volume aSAH was, respectively, higher and lower than the Hb-binding capacity of CSF haptoglobin.ConclusionThe HP2 allele carries a favourable long-term prognosis after high-volume aSAH. Haptoglobin and the Hb clearance pathway are therapeutic targets after aSAH.

Auditory deficits are increasingly recognised following aneurysmal subarachnoid haemorrhage (aSAH) and are thought to be of central rather than peripheral origin. Central hearing impairment, also known as auditory processing disorder (APD), often coexists with cognitive deficits and it is thought that APD has both auditory and cognitive elements. The aim of this study was to assess auditory outcome following aSAH and its relationship with cognition. A retrospective case-controlled study design was employed with aSAH cases and matched controls identified from the UK Biobank. Auditory and cognitive outcomes were assessed using the digit triplet test (DTT) and a test of psychomotor reaction time, respectively. Best DTT score was compared between cases and controls using the t-test. A regression-based mediation analysis was performed to assess whether cognition mediated auditory outcome. 270 aSAH patients with auditory outcomes were identified with an average follow-up of 106 months. A matched control cohort of 1080 individuals was also identified. The aSAH cohort had significantly impaired best DTT scores compared to matched controls (p = 0.002). Cognition significantly mediated auditory outcome following aSAH, accounting for 9.8% of the hearing impairment after aSAH. In conclusion significant hearing impairment follows aSAH. The deficit is bilateral and non-progressive. There is a link with cognitive deficit, pointing to a central rather than peripheral source, in keeping with an auditory processing disorder. All aSAH patients should be asked about hearing difficulty at follow-up and when present it should be investigated with peripheral and central auditory assessments, as well as cognitive tests.Keywords: Health care; Hearing loss; Outcome assessment; Stroke; Subarachnoid haemorrhage.

Objective: the aim of this study was to provide the evidence base to guide interconversion of the modified Rankin Scale (mRS) and Glasgow Outcome Scale (GOS) in neurological research. Methods: a retrospective analysis of paired mRS and GOS recordings was conducted using datasets with the following selection criteria: (1) patients had haemorrhagic stroke, (2) simultaneous mRS and GOS measurements were available, and (3) data sharing was possible. The relationship between mRS and GOS was assessed using correlation analysis. The optimum dichotomisation thresholds for agreement between the mRS and GOS were identified using Cohen's kappa coefficient. Two-way conversion tables between mRS and GOS were developed based on the highest agreement between scores. Finally, to identify which direction of conversion (mRS to GOS or vice versa) was better, the Kolmogorov-Smirnov D statistic was calculated. Results: using 3474 paired recordings the mRS and GOS were shown to be highly correlated (ρ = 0.90, p < 0.0001). The greatest agreement between the two scoring systems occurred when mRS=0-2 and GOS=4-5 was used to define good outcome (κ=0.83, 95% confidence interval: 0.81–0.85). Converting from mRS to GOS was better than the reverse direction as evidenced by a lower Kolmogorov-Smirnov statistic (D=0.054 compared to D=0.157). Conclusions: this study demonstrates that the mRS and GOS are highly correlated, establishes the optimum dichotomisation threshold for agreement, provides a method for interconversion and shows that mRS to GOS conversion is superior to the reverse direction if a choice is available.

Background and Purpose: Dural arteriovenous fistulae can present with hemorrhage, but there remains a paucity of data regarding subsequent outcomes. We sought to use the CONDOR (Consortium for Dural Arteriovenous Fistula Outcomes Research), a multi-institutional registry, to characterize the morbidity and mortality of dural arteriovenous fistula–related hemorrhage. Methods: A retrospective review of patients in CONDOR who presented with dural arteriovenous fistula–related hemorrhage was performed. Patient characteristics, clinical follow-up, and radiographic details were analyzed for associations with poor outcome (defined as modified Rankin Scale score ≥3). Results: The CONDOR dataset yielded 262 patients with incident hemorrhage, with median follow-up of 1.4 years. Poor outcome was observed in 17.0% (95% CI, 12.3%–21.7%) at follow-up, including a 3.6% (95% CI, 1.3%–6.0%) mortality. Age and anticoagulant use were associated with poor outcome on multivariable analysis (odds ratio, 1.04, odds ratio, 5.1 respectively). Subtype of hemorrhage and venous shunting pattern of the lesion did not affect outcome significantly. Conclusions: Within the CONDOR registry, dural arteriovenous fistula–related hemorrhage was associated with a relatively lower morbidity and mortality than published outcomes from other arterialized cerebrovascular lesions but still at clinically consequential rates.

Tau becomes abnormally hyper-phosphorylated and aggregated in tauopathies like Alzheimers disease (AD). As age is the greatest risk factor for developing AD, it is important to understand how tau protein itself, and the pathways implicated in its turnover, change during aging. We investigated age-related changes in total and phosphorylated tau in brain samples from two cohorts of cognitively normal individuals spanning 19-74 years, without overt neurodegeneration. One cohort utilised resected tissue and the other used post-mortem tissue. Total soluble tau levels declined with age in both cohorts. Phosphorylated tau was undetectable in the post-mortem tissue but was clearly evident in the resected tissue and did not undergo significant age-related change. To ascertain if the decline in soluble tau was correlated with age-related changes in autophagy, three markers of autophagy were tested but only two appeared to increase with age and the third was unchanged. This implies that in individuals who do not develop neurodegeneration, there is an age-related reduction in soluble tau which could potentially be due to age-related changes in autophagy. Thus, to explore how an age-related increase in autophagy might influence tau-mediated dysfunctions in vivo, autophagy was enhanced in a Drosophila model and all age-related tau phenotypes were significantly ameliorated. These data shed light on age-related physiological changes in proteins implicated in AD and highlights the need to study pathways that may be responsible for these changes. It also demonstrates the therapeutic potential of interventions that upregulate turnover of aggregate-prone proteins during aging.

Aneurysmal subarachnoid haemorrhage (aSAH) results in persistent clinical deficits which prevent survivors from returning to normal daily functioning. Only a small fraction of the variation in clinical outcome following aSAH is explained by known clinical, demographic and imaging variables; meaning additional unknown factors must play a key role in clinical outcome. There is a growing body of evidence that genetic variation is important in determining outcome following aSAH. Understanding genetic determinants of outcome will help to improve prognostic modelling, stratify patients in clinical trials and target novel strategies to treat this devastating disease. This protocol details a two-stage genome-wide association study to identify susceptibility loci for clinical outcome after aSAH using individual patient-level data from multiple international cohorts. Clinical outcome will be assessed using the modified Rankin Scale or Glasgow Outcome Scale at 1–24 months. The stage 1 discovery will involve meta-analysis of individual-level genotypes from different cohorts, controlling for key covariates. Based on statistical significance, supplemented by biological relevance, top single nucleotide polymorphisms will be selected for replication at stage 2. The study has national and local ethical approval. The results of this study will be rapidly communicated to clinicians, researchers and patients through open-access publication(s), presentation(s) at international conferences and via our patient and public network.

BACKGROUND: Low-grade intracranial dural arteriovenous fistulas (dAVF) have a benign natural history in the majority of cases. The benefit from treatment of these lesions is controversial.OBJECTIVE: To compare the outcomes of observation versus intervention for low-grade dAVFs.METHODS: We retrospectively reviewed dAVF patients from institutions participating in the CONsortium for Dural arteriovenous fistula Outcomes Research (CONDOR). Patients with low-grade (Borden type I) dAVFs were included and categorized into intervention or observation cohorts. The intervention and observation cohorts were matched in a 1:1 ratio using propensity scores. Primary outcome was modified Rankin Scale (mRS) at final follow-up. Secondary outcomes were excellent (mRS 0-1) and good (mRS 0-2) outcomes, symptomatic improvement, mortality, and obliteration at final follow-up.RESULTS: The intervention and observation cohorts comprised 230 and 125 patients, respectively. We found no differences in primary or secondary outcomes between the 2 unmatched cohorts at last follow-up (mean duration 36 mo), except obliteration rate was higher in the intervention cohort (78.5% vs 24.1%, P < .001). The matched intervention and observation cohorts each comprised 78 patients. We also found no differences in primary or secondary outcomes between the matched cohorts except obliteration was also more likely in the matched intervention cohort (P < .001). Procedural complication rates in the unmatched and matched intervention cohorts were 15.4% and 19.2%, respectively.CONCLUSION: Intervention for low-grade intracranial dAVFs achieves superior obliteration rates compared to conservative management, but it fails to improve neurological or functional outcomes. Our findings do not support the routine treatment of low-grade dAVFs.

The mechanisms underlying poor outcome following subarachnoid haemorrhage (SAH) are complex and multifactorial. They include early brain injury, spreading depolarisation, inflammation, oxidative stress, macroscopic cerebral vasospasm, and microcirculatory disturbances. Nrf2 is a global promoter of the antioxidant and anti-inflammatory response and has potential protective effects against all of these mechanisms. It has been shown to be upregulated after SAH, and Nrf2 knockout animals have poorer functional and behavioural outcomes after SAH. There are many agents known to activate the Nrf2 pathway. Of these, the actions of sulforaphane, curcumin, astaxanthin, lycopene,tert-butylhydroquinone, dimethyl fumarate, melatonin, and erythropoietin have been studied in SAH models. This review details the different mechanisms of injury after SAH including the contribution of haemoglobin (Hb) and its breakdown products. It then summarises the evidence that the Nrf2 pathway is active and protective after SAH and finally examines the evidence supporting Nrf2 upregulation as a therapy after SAH.

Background Minimally invasive surgery procedures, including stereotactic catheter aspiration and clearance of intracerebral hemorrhage (ICH) with recombinant tissue plasminogen activator hold a promise to improve outcome of supratentorial brain hemorrhage, a morbid and disabling type of stroke. A recently completed Phase III randomized trial showed improved mortality but was neutral on the primary outcome (modified Rankin scale score 0 to 3 at 1 yr). Objective To assess surgical performance and its impact on the extent of ICH evacuation and functional outcomes. Methods Univariate and multivariate models were used to assess the extent of hematoma evacuation efficacy in relation to mRS 0 to 3 outcome and postulated factors related to patient, disease, and protocol adherence in the surgical arm (n = 242) of the MISTIE trial. Results Greater ICH reduction has a higher likelihood of achieving mRS of 0 to 3 with a minimum evacuation threshold of ≤15 mL end of treatment ICH volume or ≥70% volume reduction when controlling for disease severity factors. Mortality benefit was achieved at ≤30 mL end of treatment ICH volume, or >53% volume reduction. Initial hematoma volume, history of hypertension, irregular-shaped hematoma, number of alteplase doses given, surgical protocol deviations, and catheter manipulation problems were significant factors in failing to achieve ≤15 mL goal evacuation. Greater surgeon/site experiences were associated with avoiding poor hematoma evacuation. Conclusion This is the first surgical trial reporting thresholds for reduction of ICH volume correlating with improved mortality and functional outcomes. To realize the benefit of surgery, protocol objectives, surgeon education, technical enhancements, and case selection should be focused on this goal.

ObjectivesTo determine current epidemiology and clinical characteristics of cerebrospinal fluid (CSF) shunt surgery, including revisions.MethodsA retrospective, multicentre, registry-based study was conducted based on 10 years’ data from the UK Shunt Registry, including primary and revision shunting procedures reported between 2004 and 2013. Incidence rates of primary shunts, descriptive statistics and shunt revision rates were calculated stratified by age group, geographical region and year of operation.Results41 036 procedures in 26 545 patients were submitted during the study period, including 3002 infants, 4389 children and 18 668 adults. Procedures included 20 947 (51.0%) primary shunt insertions in 20 947 patients, and 20 089 (49.0%) revision procedures. Incidence rates of primary shunt insertions for infants, children and adults were 39.5, 2.4 and 3.5 shunts per 100 000 person-years, respectively. These varied by geographical subregion and year of operation. The most common underlying diagnoses were perinatal intraventricular haemorrhage (35.3%) and malformations (33.9%) in infants, tumours (40.5%) and malformations (16.3%) in children, and tumours (24.6%), post-haemorrhagic hydrocephalus (16.2%) and idiopathic normal pressure hydrocephalus (14.2%) in adults. Ninety-day revision rates were 21.9%, 18.6% and 12.8% among infants, children and adults, respectively, while first-year revision rates were 31.0%, 25.2% and 17.4%. The main reasons for revision were underdrainage and infection, but overdrainage and mechanical failure continue to pose problems.ConclusionsOur report informs patients, carers, clinicians, providers and commissioners of healthcare, researchers and industry of the current epidemiology of shunting for CSF disorders, including the potential risks of complications and frequency of revision.