Decompressive Craniectomy versus Craniotomy for Acute Subdural Hematoma.

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.).

Gadolinium-enhanced intracranial aneurysm wall imaging and risk of aneurysm growth and rupture: a multicentre longitudinal cohort study.

OBJECTIVES: In patients with an unruptured intracranial aneurysm, gadolinium enhancement of the aneurysm wall is associated with growth and rupture. However, most previous studies did not have a longitudinal design and did not adjust for aneurysm size, which is the main predictor of aneurysm instability and the most important determinant of wall enhancement. We investigated whether aneurysm wall enhancement predicts aneurysm growth and rupture during follow-up and whether the predictive value was independent of aneurysm size. MATERIALS AND METHODS: In this multicentre longitudinal cohort study, individual patient data were obtained from twelve international cohorts. Inclusion criteria were as follows: 18 years or older with ≥ 1 untreated unruptured intracranial aneurysm < 15 mm; gadolinium-enhanced aneurysm wall imaging and MRA at baseline; and MRA or rupture during follow-up. Patients were included between November 2012 and November 2019. We calculated crude hazard ratios with 95%CI of aneurysm wall enhancement for growth (≥ 1 mm increase) or rupture and adjusted for aneurysm size. RESULTS: In 455 patients (mean age (SD), 60 (13) years; 323 (71%) women) with 559 aneurysms, growth or rupture occurred in 13/194 (6.7%) aneurysms with wall enhancement and in 9/365 (2.5%) aneurysms without enhancement (crude hazard ratio 3.1 [95%CI: 1.3-7.4], adjusted hazard ratio 1.4 [95%CI: 0.5-3.7]) with a median follow-up duration of 1.2 years. CONCLUSIONS: Gadolinium enhancement of the aneurysm wall predicts aneurysm growth or rupture during short-term follow-up, but not independent of aneurysm size. CLINICAL RELEVANCE STATEMENT: Gadolinium-enhanced aneurysm wall imaging is not recommended for short-term prediction of growth and rupture, since it appears to have no additional value to conventional predictors. KEY POINTS: • Although aneurysm wall enhancement is associated with aneurysm instability in cross-sectional studies, it remains unknown whether it predicts risk of aneurysm growth or rupture in longitudinal studies. • Gadolinium enhancement of the aneurysm wall predicts aneurysm growth or rupture during short-term follow-up, but not when adjusting for aneurysm size. • While gadolinium-enhanced aneurysm wall imaging is not recommended for short-term prediction of growth and rupture, it may hold potential for aneurysms smaller than 7 mm.

Risk of subarachnoid haemorrhage reduces with blood pressure values below hypertensive thresholds.

BACKGROUND: Hypertension is a known risk factor for subarachnoid haemorrhage (SAH). The aim of this study was to describe the relationship between blood pressure and SAH using a large cohort study and perform a meta-analysis of the published literature. METHODS: Participants in the UK Biobank were followed up via electronic records until 31 March 2017. Cox proportional hazards models were used to analyse the association between baseline blood pressure (systolic blood pressure [SBP], diastolic blood pressure [DBP] and MABP [mean arterial blood pressure]) and subsequent aneurysmal SAH. Linearity was assessed by comparing models including and excluding cubic splines. Electronic databases were searched from inception until 11 February 2022 for studies reporting on blood pressure and SAH. RESULTS: A total of 500,598 individuals were included with 539 (0.001%) suffering from aneurysmal SAH. Nonlinear models including cubic splines visually appeared linear between SBP of 110 and 180 mmHg and there was minimal difference in fit between linear and nonlinear models. When values were stratified, those with SBP 120-130 mmHg were at higher risk compared to those with SBP <120 mmHg (hazard ratio [HR] 1.41 [1.02, 1.95]). The meta-analysis demonstrated a similar increased risk of SAH in individuals with SBP 120-130 mmHg relative to those with <120 mmHg (HR 1.41 [1.17, 1.72]). A stepwise increase in risk was also seen at each subsequent threshold (130-140 mmHg: HR 1.85 [1.53, 2.24], 140-160 mmHg: HR 2.16 [1.57, 2.98], 160-180 mmHg: HR 2.81 [1.85, 4.29], >180 mmHg: HR 5.84 [1.94, 17.54]). CONCLUSIONS: The rate of SAH increases linearly with higher SBP in the general population and specifically appears lower in those with SBP <120 mmHg.

An assistive listening device improves hearing following aneurysmal subarachnoid haemorrhage.

BACKGROUND AND PURPOSE: Hearing impairment is common following aneurysmal subarachnoid haemorrhage (aSAH). Previous studies have demonstrated that auditory processing disorder (APD) is the primary underlying pathology. Assistive listening devices (ALDs) can be used to manage APD but have not been explored in aSAH. The aim of this study was to assess the benefit of an ALD for patients reporting hearing difficulty after aSAH. METHODS: This was a prospective pilot single-arm intervention study of an ALD for APD following aSAH. Patients who reported subjective hearing difficulty following aSAH were identified from the Wessex Neurological Centre aSAH database. Speech-in-noise was evaluated using the Bamford-Kowal-Bench (BKB) test under 60 and 65 dB noise conditions. BKB performance was compared with and without an ALD. Cognition was assessed using the Addenbrooke's Cognitive Examination-III. RESULTS: Fourteen aSAH patients with self-reported hearing loss were included in the analysis. Under both noise conditions the ALD significantly improved BKB performance (60 dB, Z = -3.30, p < 0.001; 65 dB, Z = -3.33, p < 0.001). There was no relationship between cognition and response to the ALD. CONCLUSIONS: This study demonstrates the marked benefit of ALDs to manage APD following aSAH, regardless of cognitive status. This finding has implications for the management of this common yet disabling deficit which impacts quality of life and employment. A further trial of ALDs in this patient group is needed to test whether these large, short-term benefits can be practically translated to the community for long-term benefit when used at home.

Quantification of blood and CSF volume to predict outcome after aneurysmal subarachnoid hemorrhage.

This study aimed to describe the relationship between blood and CSF volumes in different compartments on baseline CT after aSAH, assess if they independently predict long-term outcome, and explore their interaction with age. CT scans from patients participating in a prospective multicenter randomized controlled trial of patients with aSAH were segmented for blood and CSF volumes. The primary outcomes were the mRS, and the Subarachnoid Hemorrhage Outcome Tool (SAHOT) at day 28 and 180. Univariate regressions were conducted to identify significant predictors of poor outcomes, followed by principal component analysis to explore correlations between imaging variables and WFNS. A multivariate predictive model was then developed and optimized using stepwise regression. CT scans from 97 patients with a median delay from symptom onset of 271 min (131-547) were analyzed. Univariate analysis showed only WFNS, and total blood volume (TBV) were significant predictors of both short and long-term outcome with WFNS more predictive of mRS and TBV more predictive of SAHOT. Principal component analysis showed strong dependencies between the imaging predictors. Multivariate ordinal regression showed models with WFNS alone were most predictive of day 180 mRS and models with TBV alone were most predictive of SAHOT. TBV was the most significant measured imaging predictor of poor long-term outcome after aSAH. All these imaging predictors are correlated, however, and may have multiple complex interactions necessitating larger datasets to detect if they provide any additional predictive value for long-term outcome.

Dural arteriovenous fistulas are not observed to convert to a higher grade after partial embolization.

OBJECTIVE: Borden-Shucart type I dural arteriovenous fistulas (dAVFs) lack cortical venous drainage and occasionally necessitate intervention depending on patient symptoms. Conversion is the rare transformation of a low-grade dAVF to a higher grade. Factors associated with increased risk of dAVF conversion to a higher grade are poorly understood. The authors hypothesized that partial treatment of type I dAVFs is an independent risk factor for conversion. METHODS: The multicenter Consortium for Dural Arteriovenous Fistula Outcomes Research database was used to perform a retrospective analysis of all patients with type I dAVFs. RESULTS: Three hundred fifty-eight (33.2%) of 1077 patients had type I dAVFs. Of those 358 patients, 206 received endovascular treatment and 131 were not treated. Two (2.2%) of 91 patients receiving partial endovascular treatment for a low-grade dAVF experienced conversion to a higher grade, 2 (1.5%) of 131 who were not treated experienced conversion, and none (0%) of 115 patients who received complete endovascular treatment experienced dAVF conversion. The majority of converted dAVFs localized to the transverse-sigmoid sinus and all received embolization as part of their treatment. CONCLUSIONS: Partial treatment of type I dAVFs does not appear to be significantly associated with conversion to a higher grade.

Basilar artery perforator aneurysms: a comparison with non-perforator saccular aneurysms.

BACKGROUND: Basilar artery perforator aneurysms (BAPAs) are rare. There is no systematic description of their presentation, imaging, natural history and outcomes and how these compare to conventional non-perforator aneurysms. Thus, the authors in this study aimed to compare BAPAs to non-perforator aneurysms. METHODS: Cases were identified from a prospective neurovascular database, notes and imaging retrospectively reviewed and compared to a consecutive series of patients with non-perforator aneurysms. Blood volume on CT and vessel wall imaging (VWI) were compared to controls. RESULTS: 9/739 patients with aneurysmal subarachnoid haemorrhage (aSAH) harboured BAPAs. Compared to 103 with aSAH from posterior circulation aneurysms, they were more likely to be male (6/9, p = 0.008), but of equal severity (4/9 poor grade, p = 0.736) and need of CSF drainage (5/9, p = 0.154). Blood volume was similar to controls (30.2 ml vs 26.7 ml, p = 0.716). 6/9 BAPAs were initially missed on CTA. VWI showed thick (2.9 mm ± 2.7) bright enhancement (stalk ratio 1.05 ± 0.12), similar to controls with ruptured aneurysms (0.95 ± 0.23, p = 0.551), and greater than unruptured aneurysms (0.43 ± 0.11, p < 0.001). All were initially managed conservatively. Six thrombosed spontaneously. Three grew and had difficult access with few good endovascular options and were treated through a subtemporal craniotomy without complication. None rebled. At 3 months, all presenting in poor grade were mRS 3-4 and those in good grade mRS 1-2. CONCLUSIONS: Despite their small size, BAPAs present with similar volume SAH, WFNS grade and hydrocephalus to other aneurysms. They are difficult to identify on CTA but enhance strikingly on VWI. The majority thrombosed. Initial conservative management reserving treatment for growth was associated with no rebleeds or complications.

A Systematic Review and Meta-Analysis of the Pathology Underlying Aneurysm Enhancement on Vessel Wall Imaging.

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.

Haptoglobin Treatment for Aneurysmal Subarachnoid Hemorrhage: Review and Expert Consensus on Clinical Translation.

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.

Functional effects of haemoglobin can be rescued by haptoglobin in an in vitro model of subarachnoid haemorrhage.

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 are 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 in vitro and in vivo, the 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 sub-lethal Hb concentrations, we find that 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 in surviving neurons, which may link to impaired cognition or plasticity after SAH and support the development of haptoglobin as a therapy for subarachnoid haemorrhage.

Trial of Dexamethasone for Chronic Subdural Hematoma.

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

Genetic variation in NFE2L2 is associated with outcome following aneurysmal subarachnoid haemorrhage.

BACKGROUND AND PURPOSE: Nuclear 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. METHODS: Ten 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. RESULTS: One 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 ). CONCLUSIONS: The 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.

Radiological follow-up of endovascularly treated intracranial aneurysms: a survey of current practice in the UK and Ireland.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Time to evacuation of acute subdural and extradural haematoma: prospective study before and after implementation of a major trauma centre.

Purpose: Patients with Extradural (EDH) and Acute Subdural Haematomas (ASDH) represent a subgroup of head-injured patients that gain the most from timely treatment. While treatment times for head injury overall improved since the introduction of Major Trauma Centres (MTCs), no data exists describing how the time to treatment of EDH and ASDH has changed. We, therefore, compared the evacuation of ASDH and EDH before and after the implementation of a major trauma network.Methods: Data was collected prospectively between 1 May 2006 to 31 May 2007 and 1 March 2014 to 31 March 2016. The study was carried out at University Hospital Southampton, designated MTC in 2012. Patients over 18 with ASDH or EDH requiring emergency surgery were included.Results: The median time (IQR) for decompression was 4.8h (3.9-6.6) in 2006-7 and 4.4h (3.4-5.9) in 2014-16, p = 0.386. The proportion treated within 4 hours was 32% in 2006-7, and 33% in 2014-16 (p = 1.000). Analysis showed a decrease in time for CT scan (p = 0.01) and acceptance by neurosurgery (p < 0.001). There were increases in time for transferring to hospital (p = 0.005), awaiting operating theatre (p = 0.005), and operative time (p = 0.018).Conclusions: Since the introduction of MTCs, there has been no significant reduction in time to treat this select group of patients despite reductions in time to treatment of most other trauma and head-injured patients. This may be because parts of the pathway have improved, but others haven't. It is also possible that while previously head injury was poorly served, resources were prioritised to this group so finding further gains is difficult.

Aneurysm management in patients over 80 years old with good grade subarachnoid haemorrhage.

BACKGROUND: An increasing proportion of aneurysmal subarachnoid haemorrhage (aSAH) occurs in older patients, in whom there is widespread variability in treatment rates due to a different balance of risks. Our aim was to compare outcomes of patients over 80 years old with good grade aSAH who underwent treatment of their aneurysm with those who did not. METHODS: Adult patients with good grade aSAH admitted to tertiary regional neurosciences centres contributing to the UK and Ireland Subarachnoid Haemorrhage Database (UKISAH) and a cohort of consecutive patients admitted from three regional cohorts were included for analysis. Outcomes were functional outcome at discharge, three months and survival at discharge. RESULTS: In the UKISAH, patients whose aneurysm was treated were more likely to have a favourable outcome at discharge (OR 2.34, CI 1.12-4.91, p = .02), at three months (OR 2.29, CI 1.11-4.76, p = .04), and lower mortality (10% vs. 29%, OR 0.83, CI 0.72-0.94, p < .01). In the regional cohort, a similar pattern was seen, but after correction for frailty and comorbidity there was no difference in survival (HR 0.45, CI 0.12-1.68, p = .24) or favourable outcome at discharge (OR 0.83, CI 0.23-2.94, p = .77) and at three months (OR 1.03, CI 0.25-4.29, p = .99). CONCLUSIONS: Better early functional outcomes in those undergoing aneurysm treatment appear to be explained by differences in frailty and comorbidity. Therefore, treatment decisions in this patient group are finely balanced with no clear evidence overall of either benefit or harm in this cohort.

A survey of the radiological follow-up of unruptured intracranial aneurysms in the United Kingdom.

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.

The Haptoglobin Response after Aneurysmal Subarachnoid Haemorrhage.

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.

Iron Deposition in the Brain After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: After aneurysmal subarachnoid hemorrhage (SAH), thrombus forms over the cerebral cortex and releases hemoglobin. When extracellular, hemoglobin is toxic to neurones. High local hemoglobin concentration overwhelms the clearance capacity of macrophages expressing the hemoglobin-haptoglobin scavenger receptor CD163. We hypothesized that iron is deposited in the cortex after SAH and would associate with outcome. METHODS: Two complementary cross-sectional studies were conducted. Postmortem brain tissue from 39 SAH (mean postictal interval of 9 days) and 22 control cases was studied with Perls' staining for iron and immunolabeling for CD163, ADAM17 (a disintegrin and metallopeptidase domain 17), CD68, and Iba1 (ionized calcium binding adaptor molecule 1). In parallel, to study the persistence of cortical iron and its relationship to clinical outcome, we conducted a susceptibility-weighted imaging study of 21 SAH patients 6 months postictus and 10 control individuals. RESULTS: In brain tissue from patients dying soon after SAH, the distribution of iron deposition followed a gradient that diminished with distance from the brain surface. Iron was located intracellularly (mainly in macrophages, and occasionally in microglia, neurones, and glial cells) and extracellularly. Microglial activation and motility markers were increased after SAH, with a similar inward diminishing gradient. In controls, there was a positive correlation between CD163 and iron, which was lost after SAH. In SAH survivors, iron-sensitive imaging 6 months post-SAH confirmed persistence of cortical iron, related to the size and location of the blood clot immediately after SAH, and associated with cognitive outcome. CONCLUSIONS: After SAH, iron deposits in the cortical gray matter in a pattern that reflects proximity to the brain surface and thrombus and is related to cognitive outcome. These observations support therapeutic manoeuvres which prevent the permeation of hemoglobin into the cortex after SAH.

Risk of Early Versus Later Rebleeding From Dural Arteriovenous Fistulas With Cortical Venous Drainage.

BACKGROUND: Cranial dural arteriovenous fistulas with cortical venous drainage are rare lesions that can present with hemorrhage. A high rate of rebleeding in the early period following hemorrhage has been reported, but published long-term rates are much lower. No study has examined how risk of rebleeding changes over time. Our objective was to quantify the relative incidence of rebleeding in the early and later periods following hemorrhage. METHODS: Patients with dural arteriovenous fistula and cortical venous drainage presenting with hemorrhage were identified from the multinational CONDOR (Consortium for Dural Fistula Outcomes Research) database. Natural history follow-up was defined as time from hemorrhage to first treatment, rebleed, or last follow-up. Rebleeding in the first 2 weeks and first year were compared using incidence rate ratio and difference. RESULTS: Of 1077 patients, 250 met the inclusion criteria and had 95 cumulative person-years natural history follow-up. The overall annualized rebleed rate was 7.3% (95% CI, 3.2-14.5). The incidence rate of rebleeding in the first 2 weeks was 0.0011 per person-day; an early rebleed risk of 1.6% in the first 14 days (95% CI, 0.3-5.1). For the remainder of the first year, the incidence rate was 0.00015 per person-day; a rebleed rate of 5.3% (CI, 1.7-12.4) over 1 year. The incidence rate ratio was 7.3 (95% CI, 1.4-37.7; P, 0.026). CONCLUSIONS: The risk of rebleeding of a dural arteriovenous fistula with cortical venous drainage presenting with hemorrhage is increased in the first 2 weeks justifying early treatment. However, the magnitude of this increase may be considerably lower than previously thought. Treatment within 5 days was associated with a low rate of rebleeding and appears an appropriate timeframe.

Long-term fatigue following aneurysmal subarachnoid haemorrhage and the impact on employment.

BACKGROUND AND PURPOSE: Fatigue 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. METHODS: This 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. RESULTS: Fatigue is more common following aSAH compared to matched controls (aSAH 18.7%; controls 13.7%; χ2  = 13.0, p < 0.001) at a mean follow-up of 123 months. Fatigue gradually improves over time with significant fatigue decreasing by 50% from ~20% in the first year to ~10% after a decade (p = 0.04). Fatigue significantly mediated 24.0% of the effect of aSAH status on employment. CONCLUSIONS: Fatigue 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.