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Objective To estimate the cost-effectiveness of craniotomy, compared with decompressive craniectomy (DC) in UK patients undergoing evacuation of acute subdural haematoma (ASDH).Design Economic evaluation undertaken using health resource use and outcome data from the 12-month multicentre, pragmatic, parallel-group, randomised, Randomised Evaluation of Surgery with Craniectomy for Patients Undergoing Evacuation-ASDH trial.Setting UK secondary care.Participants 248 UK patients undergoing surgery for traumatic ASDH were randomised to craniotomy (N=126) or DC (N=122).Interventions Surgical evacuation via craniotomy (bone flap replaced) or DC (bone flap left out with a view to replace later: cranioplasty surgery).Main outcome measures In the base-case analysis, costs were estimated from a National Health Service and Personal Social Services perspective. Outcomes were assessed via the quality-adjusted life-years (QALY) derived from the EuroQoL 5-Dimension 5-Level questionnaire (cost-utility analysis) and the Extended Glasgow Outcome Scale (GOSE) (cost-effectiveness analysis). Multiple imputation and regression analyses were conducted to estimate the mean incremental cost and effect of craniotomy compared with DC. The most cost-effective option was selected, irrespective of the level of statistical significance as is argued by economists.Results In the cost-utility analysis, the mean incremental cost of craniotomy compared with DC was estimated to be −£5520 (95% CI −£18 060 to £7020) with a mean QALY gain of 0.093 (95% CI 0.029 to 0.156). In the cost-effectiveness analysis, the mean incremental cost was estimated to be −£4536 (95% CI −£17 374 to £8301) with an OR of 1.682 (95% CI 0.995 to 2.842) for a favourable outcome on the GOSE.Conclusions In a UK population with traumatic ASDH, craniotomy was estimated to be cost-effective compared with DC: craniotomy was estimated to have a lower mean cost, higher mean QALY gain and higher probability of a more favourable outcome on the GOSE (though not all estimated differences between the two approaches were statistically significant).Ethics Ethical approval for the trial was obtained from the North West—Haydock Research Ethics Committee in the UK on 17 July 2014 (14/NW/1076).Trial registration number ISRCTN87370545.

Background Chronic subdural haematoma is a collection of ‘old blood’ and its breakdown products in the subdural space and predominantly affects older people. Surgical evacuation remains the mainstay in the management of symptomatic cases. Objective The Dex-CSDH (DEXamethasone in Chronic SubDural Haematoma) randomised trial investigated the clinical effectiveness and cost-effectiveness of dexamethasone in patients with a symptomatic chronic subdural haematoma. Design This was a parallel, superiority, multicentre, pragmatic, randomised controlled trial. Assigned treatment was administered in a double-blind fashion. Outcome assessors were also blinded to treatment allocation. Setting Neurosurgical units in the UK. Participants Eligible participants included adults (aged ≥ 18 years) admitted to a neurosurgical unit with a symptomatic chronic subdural haematoma confirmed on cranial imaging. Interventions Participants were randomly assigned in a 1 : 1 allocation to a 2-week tapering course of dexamethasone or placebo alongside standard care. Main outcome measures The primary outcome was the Modified Rankin Scale score at 6 months dichotomised to a favourable (score of 0–3) or an unfavourable (score of 4–6) outcome. Secondary outcomes included the Modified Rankin Scale score at discharge and 3 months; number of chronic subdural haematoma-related surgical interventions undertaken during the index and subsequent admissions; Barthel Index and EuroQol 5-Dimension 5-Level utility index score reported at discharge, 3 months and 6 months; Glasgow Coma Scale score reported at discharge and 6 months; mortality at 30 days and 6 months; length of stay; discharge destination; and adverse events. An economic evaluation was also undertaken, during which the net monetary benefit was estimated at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year. Results A total of 748 patients were included after randomisation: 375 were assigned to dexamethasone and 373 were assigned to placebo. The mean age of the patients was 74 years and 94% underwent evacuation of their chronic subdural haematoma during the trial period. A total of 680 patients (91%) had 6-month primary outcome data available for analysis: 339 in the placebo arm and 341 in the dexamethasone arm. On a modified intention-to-treat analysis of the full study population, there was an absolute reduction in the proportion of favourable outcomes of 6.4% (95% confidence interval 11.4% to 1.4%; p = 0.01) in the dexamethasone arm compared with the control arm at 6 months. At 3 months, the between-group difference was also in favour of placebo (−8.2%, 95% confidence interval −13.3% to −3.1%). Serious adverse events occurred in 60 out of 375 (16.0%) in the dexamethasone arm and 24 out of 373 (6.4%) in the placebo arm. The net monetary benefit of dexamethasone compared with placebo was estimated to be –£97.19. Conclusions This trial reports a higher rate of unfavourable outcomes at 6 months, and a higher rate of serious adverse events, in the dexamethasone arm than in the placebo arm. Dexamethasone was also not estimated to be cost-effective. Therefore, dexamethasone cannot be recommended for the treatment of chronic subdural haematoma in this population group. Future work and limitations A total of 94% of individuals underwent surgery, meaning that this trial does not fully define the role of dexamethasone in conservatively managed haematomas, which is a potential area for future study. Trial registration This trial is registered as ISRCTN80782810. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/15/02) and is published in full in Health Technology Assessment; Vol. 28, No. 12. See the NIHR Funding and Awards website for further award information. Plain language summary Chronic subdural haematoma is one of the most common conditions managed in adult neurosurgery and mainly affects older people. It is an ‘old’ collection of blood and blood breakdown products found on the surface of the brain. Surgery to drain the liquid collection is effective, with most patients improving. Given that inflammation is involved in the disease process, a commonly used steroid, dexamethasone, has been used alongside surgery or instead of surgery since the 1970s. However, there is no consensus or high-quality studies confirming the effectiveness of dexamethasone for the treatment of chronic subdural haematoma. This study was designed to determine the effectiveness of adding dexamethasone to the normal treatment for patients with a symptomatic chronic subdural haematoma. The benefit of adding dexamethasone was measured using a disability score called the Modified Rankin Scale, which can be divided into favourable and unfavourable outcomes. This was assessed at 6 months after entry into the study. In total, 748 adults with a symptomatic chronic subdural haematoma treated in neurosurgical units in the UK participated. Each participant had an equal chance of receiving either dexamethasone or a placebo because they were assigned randomly. Neither the patients nor the investigators knew who received dexamethasone and who received placebo. Most patients in both groups had an operation to drain the haematoma and experienced significant functional improvement at 6 months compared with their initial admission to hospital. However, patients who received dexamethasone had a lower chance than patients who received placebo of favourable recovery at 6 months. Specifically, 84% of patients who received dexamethasone had recovered well at 6 months, compared with 90% of patients who received placebo. There were more complications in the group that received dexamethasone. This trial demonstrates that adding dexamethasone to standard treatment reduced the chance of a favourable outcome compared with standard treatment alone. Therefore, this study does not support the use of dexamethasone in treating patients with a symptomatic chronic subdural haematoma. Scientific summary Background Chronic subdural haematoma (CSDH) is a common neurological disorder predominantly affecting older people, affecting approximately 5000 people aged over 65 years in the UK each year. Its incidence is increasing owing to an ageing population, alongside the growing use of antithrombotic agents. The majority of CSDHs do not cause symptoms and are managed conservatively. In those that do cause symptoms, surgical evacuation remains the mainstay of management, which achieves a good recovery in approximately 80% of patients. The remaining 10–20% of patients may suffer a recurrence, requiring further surgery. Additional and alternative measures to surgery are sought to improve outcomes in this patient group. Inflammation has been implicated in the pathogenesis of CSDHs, which suggests a role for anti-inflammatory medications, such as steroids. Therefore, steroids may serve as a useful adjunct or even alternative to surgery. However, to date, there is a lack of high-quality evidence in the form of a randomised clinical trial or meta-analysis. This trial investigates the clinical effectiveness of a steroid, dexamethasone, in patients with symptomatic CSDH. Objectives Primary objective The primary objective of the trial was to determine the clinical effectiveness of a 2-week course of dexamethasone for adult patients with a symptomatic CSDH, assessed by comparing the rate of favourable outcomes [defined as a Modified Rankin Scale (mRS) score of 0–3] at 6 months after randomisation between the treatment and the control arm. This outcome was reviewed centrally by a clinically trained investigator blinded to treatment allocation. Secondary objectives The secondary objectives were to compare the following outcomes between the treatment and the control arm of the trial: number of CSDH-related surgical interventions undertaken during the index admission number of CSDH-related surgical interventions undertaken during subsequent admissions in the follow-up period Glasgow Coma Scale (GCS) score at discharge from the neurosurgical unit (NSU) and at 6 months Modified Rankin Scale score at discharge from the NSU and at 3 months Barthel Index score at discharge from the NSU and at 3 and 6 months mortality (30 days and 6 months) EuroQol-5 Dimensions, five-level version (EQ-5D-5L), utility index at discharge from the NSU and at 3 and 6 months length of stay in the NSU discharge destination from the NSU length of stay in secondary care rates of adverse events (AEs). An economic evaluation was also undertaken to estimate the cost-effectiveness of dexamethasone compared with placebo. Tertiary objectives Postoperative recurrence is a tertiary outcome measure and is defined as a symptomatic recurrence requiring reoperation of a previously evacuated ipsilateral CSDH. Methods Trial design The Dex-CSDH (DEXamethasone in Chronic SubDural Haematoma) trial is a multicentre, pragmatic, clinical phase III, randomised, double-blind, placebo-controlled trial of a tapering 2-week course of dexamethasone in patients with a symptomatic CSDH. The pragmatic design meant that the trial ran in parallel with standard clinical care, with the only difference being the addition of the trial drug (dexamethasone) or placebo. Intervention Two-week tapering course of dexamethasone (with matching placebo as the control). Participants Participants were screened for eligibility from 23 NSUs across the UK, with the admitting neurosurgical team determining eligibility for participation. Participants were adult patients aged ≥ 18 years with a symptomatic CSDH confirmed on cranial imaging (computerised tomography or magnetic resonance imaging of the brain). The patient or their legal representative had to provide informed consent. In the absence of a legal representative, an independent healthcare professional provided authorisation for enrolment. Patients were excluded in the presence of any of the following criteria: presence of a condition for which steroids are clearly contraindicated patients who are (or within 1 month of) receiving regular oral or intravenous glucocorticoid steroids (this did not include inhaled or topical steroids, nor did it include those receiving a single intraoperative dose of dexamethasone for anti-emesis) previous enrolment in this trial for a prior episode time interval from time of admission to the NSU to first dose of trial medication exceeded 72 hours chronic subdural haematoma in the presence of a cerebrospinal fluid shunt severe lactose intolerance or a known hypersensitivity to dexamethasone or other excipients a history of psychotic disorders unwillingness to take products containing gelatine. Patients who were screened but not included in the study were recorded on a screening log and reported centrally, with both the number of failures and the reasons for failure to recruit to the trial documented. Trial procedures Patients were managed in NSUs in accordance with standard practice. In the UK, this typically includes burr hole evacuation with the use of a subdural drain for most symptomatic patients. The decision for surgery or active monitoring was made on an individual patient basis by the blinded admitting clinical team in conjunction with the patient, in keeping with the pragmatic nature of the trial. Enrolment in the trial took place irrespective of the decision to operate and the timing of surgical intervention. Patients were randomised in 1 : 1 allocation using a computer-generated randomisation schedule, stratified by site using permuted blocks of random sizes (two or four). An interactive web-based response system was used to allocate treatment packs of 62 overencapsulated 2-mg dexamethasone tablets or 62 identical placebo capsules. The enrolled participants, clinical and research team and outcome assessors were blinded to the treatment allocation. The assigned treatment was administered as part of the routine drug round by the ward nurses. Oral administration was the preferred option, but administration via a nasogastric tube was offered to those unable to swallow. The latter method required opening of the capsules for crushing of the contents, allowing potential unblinding of the ward nurse. Therefore, the content of any opened capsules was not documented in the patient notes to maintain the blinding of the neurosurgeons and research staff. Trial drug compliance was recorded through inpatient drug charts during admission or by completion of a medication diary. Data were collected at baseline (on admission to the neurosurgical department) as part of routine standard of care, on discharge from the acute NSU, at 30 days, at 3 months and at 6 months. Patients were monitored in line with routine clinical practice until discharge, and at 3 and 6 months, to score clinical outcomes. Sample size This sample size was calculated with the following assumptions: a favourable outcome rate of 80–85% in the control arm and allowing for up to 15% loss to follow-up. A target sample size of 750 patients was needed to detect an increase in favourable outcome rate from 80–85% to 88–93%, with a power of 81–92% at the 5% significance level (two sided). An 8% increase in the rate of favourable outcome (mRS score of 0–3) at 6 months represents a clinically important treatment effect. Statistical analysis Data were analysed in accordance with the prespecified statistical analysis plan that was agreed prior to unblinding of data. Outcome data were analysed using a modified intention-to-treat analysis (all patients were included as randomised, except for those who withdrew consent for participation in the trial and those lost to follow-up). The primary outcome (mRS score at 6 months) was dichotomised into favourable (0–3) or unfavourable (4–6) outcomes. Primary analysis estimated the absolute difference between the intervention arm and the control arm in the proportions achieving a favourable outcome. A normal approximation was used to produce 95% confidence intervals (CIs) and a two-sided p-value testing the null hypothesis of no difference. Secondary analysis included a logistic regression and proportional odds logistic regression of the original mRS score adjusting for baseline covariates of age and Glasgow Coma Scale (GCS) score. Economic evaluation In the base-case analysis, costs were estimated over the 6-month trial period from an NHS and a Personal Social Services perspective. Outcomes were quality-adjusted life-years (QALYs) derived from the EuroQol-5 Dimensions, five-level version (EQ-5D-5L), at NSU discharge and at the 3- and 6-month follow-ups. Analyses were undertaken to estimate the mean incremental cost and effect, and enable the net monetary benefit (NMB) (a negative score indicates that the intervention is not estimated to be cost-effective) to be calculated, along with the cost-effectiveness acceptability curve (CEAC) (probability that dexamethasone was cost-effective). NMB and CEAC values at a willingness-to-pay threshold of £20,000 per QALY are reported. Results Primary outcome An outcome of mRS score of 0–3 occurred in 286 out of 341 patients (83.9%) in the dexamethasone arm and 306 out of 339 patients (90.3%) in the placebo arm at 6 months (difference −6.4%, 95% CI −11.4% to −1.4%; p = 0.01). After adjustment for prespecified covariates (age > 70 years and GCS score on admission), the odds ratio (OR) of a favourable outcome with dexamethasone was 0.55 (95% CI 0.33 to 0.91; p = 0.022), favouring placebo. Secondary outcomes Modified Rankin Scale at discharge and 3 months At 3 months, 268 out of 322 patients (83.2%) in the dexamethasone arm and 298 out of 326 patients (91.4%) in the placebo arm had a favourable outcome, for a between-group difference of −8.2% (95% CI −13.3% to −3.1%) in favour of the placebo arm. There was no significant difference in mRS score between the two arms at discharge [255/318 (80.2%) in the dexamethasone arm and 263/316 (83.2%) in the placebo arm for a difference of −3.0% (95% CI −9.1% to 3.0%)]. Mortality At discharge, 8 out of 375 patients (2.1%) in the dexamethasone arm and 2 out of 373 patients (0.5%) in the placebo arm had died (OR 4.08, 95% CI 1.01 to 27.2). At 6 months, 30 out of 341 patients (8.8%) in the dexamethasone arm and 17 out of 339 patients (5.0%) in the placebo arm had died (OR 1.83, 95% CI 0.99 to 3.45). Number of chronic subdural haematoma-related surgical interventions undertaken The number of surgical interventions undertaken during the index admission or during subsequent admissions during the follow-up period was similar in both arms. However, in the subset of patients who received surgery, repeat surgery for recurrence of the CSDH was performed in 6 out of 349 patients (1.7%) in the dexamethasone arm and in 25 out of 350 patients (7.1%) in the placebo arm. EuroQol-5 Dimensions, five-level version, utility index (at discharge and at 3 and 6 months) The mean EQ-5D-5L, utility index scores were compared. At discharge, the difference was −0.03 (95% CI −0.07 to 0.01), favouring placebo. At 3 months, the difference was −0.07 (95% CI −0.12 to −0.02), favouring placebo. At 6 months, the difference was −0.03 (95% CI −0.09 to 0.02), favouring placebo. Glasgow Coma Scale (at discharge and at 6 months) Glasgow Coma Scale was grouped into scores of 9–12 and 13–15. The percentage of patients with a score of 13–15 was similar at discharge (99.7% in the placebo arm vs. 99.2% in the dexamethasone arm). Insufficient data at 6 months prevented analysis. Barthel Index (at discharge and at 3 and 6 months) No significant difference was seen between the placebo arm and the dexamethasone arm at discharge, 3 months or 6 months. Length of stay in the neurosurgical unit The mean length of stay was 9.03 days in the placebo arm and 9.32 days in the dexamethasone arm. Length of stay in secondary care The mean length of stay was 13.0 days in the dexamethasone arm and 13.7 days in the placebo arm, with no significant difference between the two arms (0.95, 95% CI 0.835 to 1.09; p = 0.467). Discharge destination from the neurosurgical unit No significant difference was observed between the placebo arm and the dexamethasone arm when comparing discharge destinations. Rates of adverse events The odds of an adverse event of special interest were greater in the dexamethasone arm than in the placebo arm (OR 3.40, 95% CI 1.81 to 6.85). Similarly, the odds of a serious adverse event occurring were greater in the dexamethasone arm than in the placebo arm (OR 2.49, 95% CI 1.54 to 4.15). Economic evaluation The mean incremental cost for dexamethasone was estimated to be −£143.73 (95% CI −£1793 to £1505), with a QALY of −0.012 (95% CI −0.027 to 0.003), compared with placebo. The associated NMB of dexamethasone compared with placebo was −£97.19, with an estimated 46% probability of being cost-effective. Conclusions Implications for healthcare Dexamethasone for the treatment of symptomatic CSDH resulted in a lower proportion of favourable outcomes, as measured with the mRS, and a larger number of AEs than placebo. This treatment regime was also not estimated to be cost-effective (based on the NMB). Therefore, dexamethasone is not recommended in the treatment of CSDH. Implications for research The results of our literature review indicate that this study is the first multicentre randomised controlled trial to investigate the clinical effectiveness and cost-effectiveness of dexamethasone in the management of symptomatic CSDH. It provides evidence to inform the role of dexamethasone in this condition. Trial registration This trial is registered as ISRCTN80782810. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/15/02) and is published in full in Health Technology Assessment; Vol. 28, No. 12. See the NIHR Funding and Awards website for further award information.

Abstract Studies investigating the association between acetylsalicylic acid (ASA) use and spontaneous subarachnoid haemorrhage (SAH) in the general population have produced conflicting results. The aim of this study is to clarify the relationship between SAH and ASA. We included all participants who reported on ASA use during interim examinations of the Framingham Heart Study Cohorts. Using Cox proportional-hazards regression modelling, we estimated the hazard ratio (HR) associated with ASA use. 7692 participants were included in this study. There were 30 cases of SAH during follow up, with an estimated incidence of 10.0 per 100,000 person- years (CI 6.90–14.15). Univariate analysis showed no association between regular ASA use and SAH (HR, 0.33 [0.08–1.41]; p = 0.14). This was similar when accounting for smoking (HR, 0.35 [0.08–1.51]; p = 0.16). Using a large longitudinal dataset from the Framingham Heart Study, we observed some evidence suggesting fewer SAH in those participants taking regular ASA. However, multivariate statistical analysis showed no significant association between ASA use and SAH. Due to the low incidence of SAH in the general population, the absolute number of SAH events was low and it remains uncertain if a significant effect would become apparent with more follow up.

Introduction Dural arteriovenous fistulas (dAVFs) have been associated with rapidly progressive dementia in relatively young patients. However, the specific angioarchitecture and characteristics of these dAVFs remain to be fully described. To better understand the specific characteristics of dAVFs associated with cognitive impairment (dAVF‐CI), we utilized the CONDOR multicenter database, which provides a large cohort of dAVF available. By analyzing data from patients with dAVFs‐ CI, we aimed to identify the key features distinguishing these cases and elaborate on the pathophysiology of dAVF‐CI. Methods CONDOR is an international multicenter database comprising 1077 (dAVFs) from 14 international centers. We conducted a retrospective analysis of the CONDOR database, focusing on patients diagnosed with dAVFs‐CI. Propensity score matching analysis was performed to compare Borden type II and type III dAVFs with and without cognitive impairment as control groups. Only dAVFs with cortical venous drainage were included as this aggressive subtype can present with non‐hemorrhagic neurologic deficits. Additionally, logistic regression was then employed to identify significant characteristics associated with dAVF‐CI. Results A total of 60 patients with dAVF‐CI and 60 control dAVFs were included in the analysis. The patients with dAVF‐CI had a mean age of 58 ± 18 years. It was found that all cases of dAVF‐CI exhibited venous hypertension. Additionally, there was a significant association between sinus stenosis and dAVF‐CI (OR: 2.85, 95% CI: 1.16‐7.55, p = 0.027). Moreover, dAVF‐CI cases were characterized by the presence of multiple arteriovenous shunts, with more arterial feeders (OR 1.56, 95% CI 1.22‐2.05, p

Intracranial aneurysms are common, but only a minority rupture and cause subarachnoid haemorrhage, presenting a dilemma regarding which to treat. Vessel wall imaging (VWI) is a contrast-enhanced magnetic resonance imaging (MRI) technique used to identify unstable aneurysms. The pathological basis of MR enhancement of aneurysms is the subject of debate. This review synthesises the literature to determine the pathological basis of VWI enhancement. PubMed and Embase searches were performed for studies reporting VWI of intracranial aneurysms and their correlated histological analysis. The risk of bias was assessed. Calculations of interdependence, univariate and multivariate analysis were performed. Of 228 publications identified, 7 met the eligibility criteria. Individual aneurysm data were extracted for 72 out of a total of 81 aneurysms. Univariate analysis showed macrophage markers (CD68 and MPO, p = 0.001 and p = 0.002), endothelial cell markers (CD34 and CD31, p = 0.007 and p = 0.003), glycans (Alcian blue, p = 0.003) and wall thickness (p = 0.030) were positively associated with enhancement. Aneurysm enhancement therefore appears to be associated with inflammatory infiltrate and neovascularisation. However, all these markers are correlated with each other, and the literature is limited in terms of the numbers of aneurysms analysed and the parameters considered. The data are therefore insufficient to determine if these associations are independent of each other or of aneurysm size, wall thickness and rupture status. Thus, the cause of aneurysm-wall enhancement currently remains unknown.

Introduction The top research priority for cavernoma, identified by a James Lind Alliance Priority setting partnership was ‘Does treatment (with neurosurgery or stereotactic radiosurgery) or no treatment improve outcome for people diagnosed with a cavernoma?’ This pilot randomised controlled trial (RCT) aims to determine the feasibility of answering this question in a main phase RCT.Methods and analysis We will perform a pilot phase, parallel group, pragmatic RCT involving approximately 60 children or adults with mental capacity, resident in the UK or Ireland, with an unresected symptomatic brain cavernoma. Participants will be randomised by web-based randomisation 1:1 to treatment with medical management and with surgery (neurosurgery or stereotactic radiosurgery) versus medical management alone, stratified by prerandomisation preference for type of surgery. In addition to 13 feasibility outcomes, the primary clinical outcome is symptomatic intracranial haemorrhage or new persistent/progressive focal neurological deficit measured at 6 monthly intervals. An integrated QuinteT Recruitment Intervention (QRI) evaluates screening logs, audio recordings of recruitment discussions, and interviews with recruiters and patients/parents/carers to identify and address barriers to participation. A Patient Advisory Group has codesigned the study and will oversee its progress.Ethics and dissemination This study was approved by the Yorkshire and The Humber—Leeds East Research Ethics Committee (21/YH/0046). We will submit manuscripts to peer-reviewed journals, describing the findings of the QRI and the Cavernomas: A Randomised Evaluation (CARE) pilot trial. We will present at national specialty meetings. We will disseminate a plain English summary of the findings of the CARE pilot trial to participants and public audiences with input from, and acknowledgement of, the Patient Advisory Group.Trial registration number ISRCTN41647111.

Haptoglobin is the body’s first line of defence against the toxicity of extracellular haemoglobin released following a subarachnoid haemorrhage (SAH). We investigated the haptoglobin response after SAH in cerebrospinal fluid (CSF) and serum. Paired CSF and serum samples from 19 controls and 92 SAH patients were assayed as follows: ultra-performance liquid chromatography for CSF haemoglobin and haptoglobin, immunoassay for serum haptoglobin and multiplexed CSF cytokines, and colorimetry for albumin. There was marked CSF haptoglobin deficiency: 99% of extracellular haemoglobin was unbound. The quotients for both CSF/serum albumin (qAlb) and haptoglobin (qHp) were used to compute the CSF haptoglobin index (qHp/qAlb). CSF from SAH patients had a significantly lower haptoglobin index compared to controls, especially in Haptoglobin-1 allele carriers. Serum haptoglobin levels increased after SAH and were correlated with CSF cytokine levels. Haptoglobin variables were not associated with long-term clinical outcomes post-SAH. We conclude that: (1) intrathecal haptoglobin consumption occurs after SAH, more so in haptoglobin-1 allele carriers; (2) serum haptoglobin is upregulated after SAH, in keeping with the liver acute phase response to central inflammation; (3) haptoglobin in the CSF is so low that any variation is too small for this to affect long-term outcomes, emphasising the potential for therapeutic haptoglobin supplementation.

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.

Abstract Background Traumatic brain injury is a leading cause of death and disability worldwide. The nitric oxide synthase inhibitor Ronopterin was shown to improve clinical outcome by enhancing neuroprotection in a phase IIa trial. Methods/design The NOSTRA phase III trial (Ronopterin in traumatic brain injury) is a multi-centre, prospective, randomised, double-blinded, placebo-controlled, phase III trial in Europe. It aims at determining whether the administration of Ronopterin compared to placebo improves neurological outcome in patients with moderate or severe traumatic brain injury at 6 months after injury. The trial is designed to recruit patients between 18 and 60 years of age with moderate or severe traumatic brain injury (Glasgow Coma Scale score ≥ 3) and requiring insertion of an intracranial pressure probe. Trial patients will receive a 48-h intravenous infusion of either Ronopterin or placebo starting at the earliest 6 h and at the latest 18 h after injury. The primary outcome will be the extended Glasgow Outcome Score (eGOS) at 6 months. Secondary outcomes will include the Quality of Life Index (QOLIBRI) at 6 months after the injury and the eGOS at 3 months after the injury. Additionally, effects on mortality, intracranial pressure and cerebral perfusion pressure are evaluated. Discussion The trial aims to provide evidence on the efficacy and safety of Ronopterin in patients with traumatic brain injury. Trial registration EudraCT, 2013–003368-29. Registered on 9 March 2016. ClinicalTrials.gov, NCT02794168. Registered on 8 June 2016. Protocol version 14.0 from 05 November 2018.

Abstract 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.

The use of hyperspectral imaging for medical applications is becoming more common in recent years. One of the main obstacles that researchers find when developing hyperspectral algorithms for medical applications is the lack of specific, publicly available, and hyperspectral medical data. The work described in this paper was developed within the framework of the European project HELICoiD (HypErspectraL Imaging Cancer Detection), which had as a main goal the application of hyperspectral imaging to the delineation of brain tumors in real-time during neurosurgical operations. In this paper, the methodology followed to generate the first hyperspectral database of in-vivo human brain tissues is presented. Data was acquired employing a customized hyperspectral acquisition system capable of capturing information in the Visual and Near InfraRed (VNIR) range from 400 to 1000 nm. Repeatability was assessed for the cases where two images of the same scene were captured consecutively. The analysis reveals that the system works more efficiently in the spectral range between 450 and 900 nm. A total of 36 hyperspectral images from 22 different patients were obtained. From these data, more than 300 000 spectral signatures were labeled employing a semi-automatic methodology based on the spectral angle mapper algorithm. Four different classes were defined: normal tissue, tumor tissue, blood vessel, and background elements. All the hyperspectral data has been made available in a public repository.

Abstract Background Chronic subdural haematoma (CSDH) is a common neurosurgical condition, typically treated with surgical drainage of the haematoma. However, surgery is associated with mortality and morbidity, including up to 20% recurrence of the CSDH. Steroids, such as dexamethasone, have been identified as a potential therapy for reducing recurrence risk in surgically treated CSDHs. They have also been used as a conservative treatment option, thereby avoiding surgery altogether. The hypothesis of the Dex-CSDH trial is that a two-week course of dexamethasone in symptomatic patients with CSDH will lead to better functional outcome at six months. This is anticipated to occur through reduced number of hospital admissions and surgical interventions. Methods Dex-CSDH is a UK multi-centre, double-blind randomised controlled trial of dexamethasone versus placebo for symptomatic adult patients diagnosed with CSDH. A sample size of 750 patients has been determined, including an initial internal pilot phase of 100 patients to confirm recruitment feasibility. Patients must be recruited within 72 h of admission to a neurosurgical unit and exclusions include patients already on steroids or with steroid contraindications, patients who have a cerebrospinal fluid shunt and those with a history of psychosis. The decision regarding surgical intervention will be made by the clinical team and patients can be included in the trial regardless of whether operative treatment is planned or has been performed. The primary outcome measure is the modified Rankin Scale (mRS) at six months. Secondary outcomes include the number of CSDH-related surgical interventions during follow-up, length of hospital stay, mRS at three months, EQ-5D at three and six months, adverse events, mortality and a health-economic analysis. Discussion This multi-centre trial will provide high-quality evidence as to the effectiveness of dexamethasone in the treatment of CSDH. This has implications for patient morbidity and mortality as well as a potential economic impact on the overall health service burden from this condition. Trial registration ISRCTN, ISRCTN80782810. Registered on 7 November 2014. EudraCT, 2014-004948-35. Registered on 20 March 2015. Dex-CSDH trial protocol version 3, 27 Apr 2017. This protocol was developed in accordance with the SPIRIT checklist. Available as a separate document on request.

Abstract 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.

After publication of our article [1] the authors have notified us that one of the names has been incorrectly spelled.

Surgery for brain cancer is a major problem in neurosurgery. The diffuse infiltration into the surrounding normal brain by these tumors makes their accurate identification by the naked eye difficult. Since surgery is the common treatment for brain cancer, an accurate radical resection of the tumor leads to improved survival rates for patients. However, the identification of the tumor boundaries during surgery is challenging. Hyperspectral imaging is a non-contact, non-ionizing and non-invasive technique suitable for medical diagnosis. This study presents the development of a novel classification method taking into account the spatial and spectral characteristics of the hyperspectral images to help neurosurgeons to accurately determine the tumor boundaries in surgical-time during the resection, avoiding excessive excision of normal tissue or unintentionally leaving residual tumor. The algorithm proposed in this study to approach an efficient solution consists of a hybrid framework that combines both supervised and unsupervised machine learning methods. Firstly, a supervised pixel-wise classification using a Support Vector Machine classifier is performed. The generated classification map is spatially homogenized using a one-band representation of the HS cube, employing the Fixed Reference t-Stochastic Neighbors Embedding dimensional reduction algorithm, and performing a K-Nearest Neighbors filtering. The information generated by the supervised stage is combined with a segmentation map obtained via unsupervised clustering employing a Hierarchical K-Means algorithm. The fusion is performed using a majority voting approach that associates each cluster with a certain class. To evaluate the proposed approach, five hyperspectral images of surface of the brain affected by glioblastoma tumor in vivo from five different patients have been used. The final classification maps obtained have been analyzed and validated by specialists. These preliminary results are promising, obtaining an accurate delineation of the tumor area.

After publication of the original article [1], the authors notified that that one of the BNTRC institutional collaborator names was misspelled.

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.

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: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Evoked tympanic membrane displacement (TMD) is a non-invasive technique for assessing intracranial pressure (ICP). The aim of this study was to define reference intervals (RIs) in the healthy population. Approach: Measurements were made in 154 healthy adults. Results were quantified by Vm, which is the most frequently described TMD measurement. Distributions were determined for sitting and supine posture. Differences between right and left ears were explored using a Wilcoxon signed-rank test. Postural changes were used to assess pressure transfer between the cerebral spinal fluid (CSF) and the perilymph. Main results: The range in which 95% of scores fall is  −283 to 722 nl (M  =  132 nl) left sitting, −232 to 623 nl (M  =  97 nl) right sitting, −543 to 717 nl (M  =  37 nl) left supine and  −584 to 504 nl (M  =  −15 nl) right supine. No significant difference was seen between the left and right ears in the sitting position; a significant difference was seen in the supine position. A significant effect of posture was seen for both the left and right ears. Postural changes indicated pressure transfer between the CSF and perilymph more often in the right ear (75.3%) than the left (61.9%). Pressure transfer could not be assumed in either ear for 13.4% of participants. Significance: We present the largest dataset of evoked TMD in healthy individuals and the first set of RIs for Vm. A patient cohort with both invasive ICP and evoked TMD measurements is needed to validate the technique for clinical use. [ABSTRACT FROM AUTHOR]