Study on prognosis of acutely ruptured intracranial aneurysms (SPARTA): a protocol for a multicentre prospective cohort study.

BACKGROUND: Ruptured intracranial aneurysms resulting in subarachnoid haemorrhage can be treated by open surgical or endovascular treatment. Despite multiple previous studies, uncertainties on the optimal treatment practice still exists. The resulting treatment variation may result in a variable, potentially worse, patient outcome. To better inform future treatment strategies, this study aims to identify the effectiveness of different treatment strategies in patients with ruptured intracranial aneurysms by investigating long-term functional outcome, complications and cost-effectiveness. An explorative analysis of the diagnostic and prognostic value of radiological imaging will also be performed. METHODS: This multi-centre observational prospective cohort study will have a follow-up of 10 years. A total of 880 adult patients with a subarachnoid haemorrhage caused by a ruptured intracranial aneurysm will be included. Calculation of sample size (N = 880) was performed to show non-inferiority of clip-reconstruction compared to endovascular treatment on 1 year outcome, assessed by using the ordinal modified Rankin Scale. The primary endpoint is the modified Rankin Scale score and mortality at 1 year after the initial subarachnoid haemorrhage. Patients will receive 'non-experimental' regular care during their hospital stay. For this study, health questionnaires and functional outcome will be assessed at baseline, before discharge and at follow-up visits. DISCUSSION: Despite the major healthcare and societal burden, the optimal treatment strategy for patients with subarachnoid haemorrhage caused by ruptured intracranial aneurysms is yet to be determined. Findings of this comparative effectiveness study, in which in-between centre variation in practice and patient outcome are investigated, will provide evidence on the effectiveness of treatment strategies, hopefully contributing to future high value treatment standardisation. TRIAL REGISTRATION NUMBER: NCT05851989 DATE OF REGISTRATION: May 10th, 2023.

Navigating PROSPERO4animals: 10 top tips for efficient pre-registration of your animal systematic review protocol.

Systematic reviews are an essential tool in identifying knowledge gaps and synthesizing evidence from in vivo animal research to improve human health. The review process follows an explicit and systematic methodology to minimize bias, but is not immune to biases or methodological flaws. Pre-registering a systematic review protocol has several benefits, including avoiding unplanned duplication of reviews, reducing reporting biases, and providing structure throughout the review process. It also helps to align the opinions of review team members and can shield researchers from post-hoc critique. PROSPERO4animals is the international prospective register of systematic reviews (PROSPERO) for the preregistration of systematic review of animal studies. As administrators, here we provide 10 tips to facilitate pre-registration in PROSPERO4animals. These tips address common difficulties that both beginners and experienced researchers may face when pre-registering their systematic review protocols. This article aims to help authors write and register a detailed systematic review protocol on PROSPERO4animals.

Dynamic Computed Tomography Angiography for capturing vessel wall motion: A phantom study for optimal image reconstruction.

BACKGROUND: Reliably capturing sub-millimeter vessel wall motion over time, using dynamic Computed Tomography Angiography (4D CTA), might provide insight in biomechanical properties of these vessels. This may improve diagnosis, prognosis, and treatment decision making in vascular pathologies. PURPOSE: The aim of this study is to determine the most suitable image reconstruction method for 4D CTA to accurately assess harmonic diameter changes of vessels. METHODS: An elastic tube (inner diameter 6 mm, wall thickness 2 mm) was exposed to sinusoidal pressure waves with a frequency of 70 beats-per-minute. Five flow amplitudes were set, resulting in increasing sinusoidal diameter changes of the elastic tube, measured during three simulated pulsation cycles, using ECG-gated 4D CTA on a 320-detector row CT system. Tomographic images were reconstructed using one of the following three reconstruction methods: hybrid iterative (Hybrid-IR), model-based iterative (MBIR) and deep-learning based (DLR) reconstruction. The three reconstruction methods where based on 180 degrees (half reconstruction mode) and 360 degrees (full reconstruction mode) raw data. The diameter change, captured by 4D CTA, was computed based on image registration. As a reference metric for diameter change measurement, a 9 MHz linear ultrasound transducer was used. The sum of relative absolute differences (SRAD) between the ultrasound and 4D CTA measurements was calculated for each reconstruction method. The standard deviation was computed across the three pulsation cycles. RESULTS: MBIR and DLR resulted in a decreased SRAD and standard deviation compared to Hybrid-IR. Full reconstruction mode resulted in a decreased SRAD and standard deviations, compared to half reconstruction mode. CONCLUSIONS: 4D CTA can capture a diameter change pattern comparable to the pattern captured by US. DLR and MBIR algorithms show more accurate results than Hybrid-IR. Reconstruction with DLR is >3 times faster, compared to reconstruction with MBIR. Full reconstruction mode is more accurate than half reconstruction mode.

Augmented reality-The way forward in patient education for intracranial aneurysms? A qualitative exploration of views, expectations and preferences of patients suffering from an unruptured intracranial aneurysm regarding augmented reality in patient education.

Objectives: The goal of this project is to explore the views, expectations and preferences of patients with an unruptured intracranial aneurysm regarding the use of AR in patient education. Methods: To gain an in-depth understanding of the patients' perspective, a face-to-face interview study was conducted using an interview protocol with a predefined topic list. All interviews were audio-recorded and transcribed verbatim afterwards. Transcripts were analyzed using thematic content analyses. Coding was performed using Atlas.ti software. Results: Seventeen interviews were conducted. The views, expectations and preferences of patients regarding patient education with AR could be subdivided into 15 categories, which could be grouped into 4 general themes: 1) experiences with current patient education, 2) expectations of AR in patient education, 3) opportunities and limitations of AR, and 4) out-of-hospital use of an AR application. Patients' expectations were predominantly positive regarding improving patients' understanding of their medical situation and doctor-patient communication. Discusssion: This study suggests that patients with unruptured intracranial aneurysms are open to receive patient education regarding their disease with AR. Patients expect that AR models can help patients with intra-cranial aneurysms better understand their disease, treatment options and risks. Additionally, patients expect AR could improve doctor-patient communication.

A systematic review of the Woven EndoBridge device-do findings in pre-clinical animal models compare to clinical results?

BACKGROUND: The Woven Endobridge (WEB) is designed to treat intracranial wide-neck bifurcation aneurysms, preventing subarachnoid hemorrhage. The translational value of animal models used for WEB device testing is unknown. With this systematic review, we aim to identify the existing animal models used in testing the WEB device and compare the efficacy and safety outcomes to those of prospective clinical studies. METHODS: This study was funded by ZonMw: project number 114024133. A comprehensive search was performed in PubMed and in EMBASE via the Ovid interface. The following exclusion criteria were used: 1) not an original full-length research paper, 2) not an in vivo animal study or a human study, 3) no WEB implantation, 4) if in humans: not a prospective study. The SYRCLE risk of bias tool (animal studies) and the Newcastle-Ottawa quality assessment scale for cohort studies (clinical studies) were used to assess risks of bias. A narrative synthesis was performed. RESULTS: Six animal studies and 17 clinical studies met the inclusion criteria. The rabbit elastase aneurysm model was the only animal model used to assess WEB device performance. Safety outcomes were never reported in animal studies. Efficacy outcomes were more heterogeneous in animal studies than in clinical studies, which could be due to limited external validity of the animal models in terms of aneurysm induction and dimensions. Both animal and clinical studies were predominantly single-arm studies, and were at unclear risk of several types of bias. CONCLUSIONS: The rabbit elastase aneurysm model was the only pre-clinical animal model used to assess WEB device performance. Safety outcomes were not evaluated in animal studies and could therefore not be compared to clinical outcomes. Efficacy outcomes were more heterogeneous in animal studies than in clinical studies. Future research should focus on improving methodology and reporting in order to draw accurate conclusions on the performance of the WEB device.

Safety and efficacy of the eCLIPs bifurcation remodelling system for the treatment of wide necked bifurcation aneurysms: 1 year results from the European eCLIPs Safety, Feasibility, and Efficacy Study (EESIS).

BACKGROUND: The eCLIPs bifurcation remodelling system is a non-circumferential implant that bridges the neck from outside of a bifurcation aneurysm. The goal of the multicenter, post-marketing European eCLIPs Safety, FeasIbility, and Efficacy Study (EESIS), was to present the efficacy and safety results of the eCLIPs device after 365 days of follow-up. METHODS: All patients were to receive an eCLIPs in conjunction with coils. The study was conducted according to good clinical practices and included independent adjudication of safety and efficacy outcomes. RESULTS: Twenty patients were enrolled at four European centers. Mean age was 60 years (range 41-74) and aneurysms were located at the basilar tip (n=19) and carotid tip (n=1). Average aneurysm dome height was 6.0 mm (range 2.0-15.0). Mean neck length was 5.1 mm (range 2.6-8.5). The technical success rate was 90% (18 of 20). No major territorial strokes or deaths occurred between the index procedure and after 365 days of follow-up. Complete occlusion was achieved in 60% of patients (12 of 20 patients) and 67% of patients with an eCLIPs device (12 of 18) after 365 days of follow-up. Adequate occlusion (complete occlusion and neck remnant) was achieved in 80% of patients (16 of 20 patients) and 89% of patients with an eCLIPs device (16 of 18 patients) after 365 days of follow-up. CONCLUSION: In this small series, treatment with eCLIPs was feasible, safe, and efficacious, considering the challenging nature of the aneurysms. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02607501.

Non-adjustable gravitational valves or adjustable valves in the treatment of hydrocephalus after aneurysmal subarachnoid hemorrhage patients?

PURPOSE: Hydrocephalus requiring permanent CSF shunting after aneurysmal subarachnoid hemorrhage (aSAH) is frequent. It is unknown which type of valve is optimal. This study evaluates if the revision rate of gravitational differential pressure valves (G-DPVs, GAV® system (B Braun)) (G-DPV) is comparable to adjustable pressure valves (Codman Medos Hakim) (APV) in the treatment of post-aSAH hydrocephalus. METHODS: The use of a gravitational differential pressure valve is placed in direct comparison with an adjustable pressure valve system. A retrospective chart review is performed to compare the revision rates for the two valve systems. RESULTS: Within the registry from Radboud University Medical Center, 641 patients with a SAH could be identified from 1 January 2013 until 1 January 2019, whereas at the Heinrich Heine University, 617 patients were identified, totaling 1258 patients who suffered from aSAH. At Radboud University Medical Center, a gravitational differential pressure valve is used, whereas at the Heinrich Heine University, an adjustable pressure valve system is used. One hundred sixty-six (13%) patients required permanent ventricular peritoneal or atrial shunting. Shunt dysfunction occurred in 36 patients: 13 patients of the 53 (25%) of the gravitational shunt cohort, and in 23 of the 113 (20%) patients with an adjustable shunt (p = 0.54). Revision was performed at a mean time of 3.2 months after implantation with the gravitational system and 8.2 months with the adjustable shunt system. Combined rates of over- and underdrainage leading to revision were 7.5% (4/53) for the gravitational and 3.5% (4/113) for the adjustable valve system (p = 0 .27). CONCLUSION: The current study does not show a benefit of a gravitational pressure valve (GAV® system) over an adjustable pressure valve (CODMAN ® HAKIM®) in the treatment of post-aSAH hydrocephalus. The overall need for revision is high and warrants further improvements in care.

Aneurysm-on-a-Chip: Setting Flow Parameters for Microfluidic Endothelial Cultures Based on Computational Fluid Dynamics Modeling of Intracranial Aneurysms.

Intracranial aneurysms are pouch-like extrusions from the vessels at the base of the brain which can rupture and cause a subarachnoid hemorrhage. The pathophysiological mechanism of aneurysm formation is thought to be a consequence of blood flow (hemodynamic) induced changes on the endothelium. In this study, the results of a personalized aneurysm-on-a-chip model using patient-specific flow parameters and patient-specific cells are presented. CT imaging was used to calculate CFD parameters using an immersed boundary method. A microfluidic device either cultured with human umbilical vein endothelial cells (HUVECs) or human induced pluripotent stem cell-derived endothelial cells (hiPSC-EC) was used. Both types of endothelial cells were exposed for 24 h to either 0.03 Pa or 1.5 Pa shear stress, corresponding to regions of low shear and high shear in the computational aneurysm model, respectively. As a control, both cell types were also cultured under static conditions for 24 h as a control. Both HUVEC and hiPSC-EC cultures presented as confluent monolayers with no particular cell alignment in static or low shear conditions. Under high shear conditions HUVEC elongated and aligned in the direction of the flow. HiPSC-EC exhibited reduced cell numbers, monolayer gap formation and cells with aberrant, spread-out morphology. Future research should focus on hiPSC-EC stabilization to allow personalized intracranial aneurysm models.

Outcomes after Flow Diverter Treatment in Subarachnoid Hemorrhage: A Meta-Analysis and Development of a Clinical Prediction Model (OUTFLOW).

BACKGROUND: patients with a subarachnoid hemorrhage (SAH) might need a flow diverter (FD) placement for complex acutely ruptured intracranial aneurysms (IAs). We conducted a meta-analysis and developed a prediction model to estimate the favorable clinical outcome after the FD treatment in acutely ruptured IAs. METHODS: a systematic literature search was performed from 2010 to January 2021 in PubMed and Embase databases. Studies with more than five patients treated with FDs within fifteen days were included. In total, 1157 studies were identified. The primary outcome measure was the favorable clinical outcome (mRS 0-2). Secondary outcome measures were complete occlusion rates, aneurysm rebleeding, permanent neurologic deficit caused by procedure-related complications, and all-cause mortality. A prediction model was constructed using individual patient-level data. RESULTS: 26 retrospective studies with 357 patients and 368 aneurysms were included. The pooled rates of the favorable clinical outcome, mortality, and complete aneurysm occlusion were 73.7% (95% CI 64.7-81.0), 17.1% (95% CI 13.3-21.8), and 85.6% (95% CI 80.4-89.6), respectively. Rebleeding occurred in 3% of aneurysms (11/368). The c-statistic of the final model was 0.83 (95% CI 0.76-0.89). All the studies provided a very low quality of evidence. CONCLUSIONS: FD treatment can be considered for complex ruptured IAs. Despite high complication rates, the pooled clinical outcomes seem favorable. The prediction model needs to be validated by larger prospective studies before clinical application.

Time trends in the risk of delayed cerebral ischemia after subarachnoid hemorrhage: a meta-analysis of randomized controlled trials.

OBJECTIVE: Delayed cerebral ischemia (DCI) contributes to morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). Continuous improvement in the management of these patients, such as neurocritical care and aneurysm repair, may decrease the prevalence of DCI. In this study, the authors aimed to investigate potential time trends in the prevalence of DCI in clinical studies of DCI within the last 20 years. METHODS: PubMed, Embase, and the Cochrane library were searched from 2000 to 2020. Randomized controlled trials that reported clinical (and radiological) DCI in patients with aSAH who were randomized to a control group receiving standard care were included. DCI prevalence was estimated by means of random-effects meta-analysis, and subgroup analyses were performed for the DCI sum score, Fisher grade, clinical grade on admission, and aneurysm treatment method. Time trends were evaluated by meta-regression. RESULTS: The search strategy yielded 5931 records, of which 58 randomized controlled trials were included. A total of 4424 patients in the control arm were included. The overall prevalence of DCI was 0.29 (95% CI 0.26-0.32). The event rate for prevalence of DCI among the high-quality studies was 0.30 (95% CI 0.25-0.34) and did not decrease over time (0.25% decline per year; 95% CI -2.49% to 1.99%, p = 0.819). DCI prevalence was higher in studies that included only higher clinical or Fisher grades, and in studies that included only clipping as the treatment modality. CONCLUSIONS: Overall DCI prevalence in patients with aSAH was 0.29 (95% CI 0.26-0.32) and did not decrease over time in the control groups of the included randomized controlled trials.

Systematic Evaluation of Spinal Cord Injury Animal Models in the Field of Biomaterials.

The large number of animal models used in spinal cord injury (SCI) research complicates the objective selection of the most appropriate model to investigate the efficacy of biomaterial-based therapies. This systematic review aims to identify a list of relevant animal models of SCI by evaluating the confirmation of SCI and animal survival in all published SCI models used in biomaterials research up until April 2021. A search in PubMed and Embase based on "spinal cord injury," "animal models," and "biomaterials" yielded 4606 papers, 393 of which were further evaluated. A total of 404 individual animal experiments were identified based on type of SCI, level of SCI, and the sex, species, and strain of the animals used. Finally, a total of 149 unique animal models were comparatively evaluated, which led to the generation of an evidence-based list of well-documented mid-thoracic rat models of SCI. These models were used most often, clearly confirmed SCI, and had relatively high survival rates, and therefore could serve as a future starting point for studying novel biomaterial-based therapies for SCI. Furthermore, the review discusses (1) the possible risk of bias in SCI animal models, (2) the difficulty in replication of such experiments due to frequent poor reporting of the methods and results, and (3) the clinical relevance of the currently utilized models. Systematic review registration: The study was prospectively registered in PROSPERO, registration number CRD42019141162. Impact statement Studies on biomaterial-based therapies within the field of spinal cord injury (SCI) research show a large inconsistency concerning the selection of animal models. This review goes beyond summarizing the existing gaps between experimental and clinical SCI by systematically evaluating all animal models used within this field. The models identified by this work were used most often, clearly confirmed SCI, and had a relatively high survival rate. This evidence-based list of well-documented animal models will serve as a practical guideline in future research on innovative biomaterial-based therapies for SCI.

Factors Associated with Subsequent Subarachnoid Hemorrhages in Patients with Multiple Intracranial Aneurysms.

BACKGROUND: Detection of multiple intracranial aneurysms (MIAs) in patients with aneurysmal subarachnoid hemorrhage (aSAH) is common and the optimal management of the additional unruptured intracranial aneurysms (UIA) is often a matter of debate. We calculate the incidence and the factors associated with subsequent aSAHs from untreated additional aneurysms in a single-center group of patients with aSAH and MIAs. METHODS: Charts of patients with MIAs admitted to our neurosurgery department for aSAH between January 2000 and March 2020 were retrospectively reviewed. Incidence rate and factors associated with subsequent aSAHs were calculated with univariable and multivariable analyses. RESULTS: Of the unruptured aneurysms, 50% were preventively treated. During a median follow-up of 3 years, 20 of 174 patients (11.5%) presented with a second aSAH. Incidence of rupture of an additional untreated aneurysm was 18.05 per 1000 person/years (confidence interval, 10.69-30.47). Rupture incidence of an additional aneurysm located in the anterior circulation was 32.70 per 1000 person/years and 40.73 per 1000 person/years in the posterior circulation. Presence of untreated mirror and de novo aneurysms increased the risk of overall subsequent aSAHs by 16.9-fold and 7.6-fold, respectively. Most untreated additional aneurysms causing a subsequent aSAH were smaller than 7 mm (73.3%), with middle cerebral artery being the most frequent location (40.0%). CONCLUSIONS: Incidence of subsequent aSAHs is high in patients with aSAH-MIA. Untreated mirror and de novo aneurysms are associated with higher rupture risk. Longer follow-up and prophylactic treatment of asymptomatic aneurysms at higher rupture risk are recommended to prevent the significant poor outcome of subsequent aSAHs.

Implementation of an Automated Cerebrospinal Fluid Drainage System for Early Mobilization in Neurosurgical Patients.

BACKGROUND: Automated cerebrospinal fluid (CSF) drainage systems allow for the mobilization of patients with an external CSF drain. The aim of this study is to describe the implementation of an automated CSF drainage system in neurosurgical patients with external CSF drains. METHODS: A feasibility study was performed using an automated CSF drainage system (LiquoGuard®7, Möller Medical GmbH, Fulda, Germany) in adult neurosurgical patients treated with external lumbar or external ventricular drains between December 2017 and June 2020. Limited mobilization was allowed-patients were allowed to adjust their inclined beds, sit in chairs and walk under the supervision of a nurse or physical therapist. The primary outcome was the number of prematurely terminated drainage sessions. RESULTS: Twenty-three patients were included. Drainage was terminated prematurely in eight (35%) patients. In three (13%) of these patients, drainage was terminated due to signs of hydrocephalus. Pressure-controlled drainage in patients with external lumbar drains (ELD) showed inaccurate pressure curves, which was solved by using volume-controlled drainage in ELD patients. CONCLUSION: The implementation of an automated CSF drainage system (LiquoGuard®7) for CSF drainage allows for early mobilization in a subset of patients with external CSF drains. External lumbar drains require volume-based drainage rather than differential pressure-dependent drainage.

Prediction Models in Aneurysmal Subarachnoid Hemorrhage: Forecasting Clinical Outcome With Artificial Intelligence.

BACKGROUND: Predicting outcome after aneurysmal subarachnoid hemorrhage (aSAH) is known to be challenging and complex. Machine learning approaches, of which feedforward artificial neural networks (ffANNs) are the most widely used, could contribute to the patient-specific outcome prediction. OBJECTIVE: To investigate the prediction capacity of an ffANN for the patient-specific clinical outcome and the occurrence of delayed cerebral ischemia (DCI) and compare those results with the predictions of 2 internationally used scoring systems. METHODS: A prospective database was used to predict (1) death during hospitalization (ie, mortality) (n = 451), (2) unfavorable modified Rankin Scale (mRS) at 6 mo (n = 413), and (3) the occurrence of DCI (n = 362). Additionally, the predictive capacities of the ffANN were compared to those of Subarachnoid Haemorrhage International Trialists (SAHIT) and VASOGRADE to predict clinical outcome and occurrence of DCI. RESULTS: The area under the curve (AUC) of the ffANN showed to be 88%, 85%, and 72% for predicting mortality, an unfavorable mRS, and the occurrence of DCI, respectively. Sensitivity/specificity rates of the ffANN for mortality, unfavorable mRS, and the occurrence of DCI were 82%/80%, 94%/80%, and 74%/68%. The ffANN and SAHIT calculator showed similar AUCs for predicting personalized outcome. The presented ffANN and VASOGRADE were found to perform equally with regard to personalized prediction of occurrence of DCI. CONCLUSION: The presented ffANN showed equal performance when compared with VASOGRADE and SAHIT scoring systems while using less individual cases. The web interface launched simultaneously with the publication of this manuscript allows for usage of the ffANN-based prediction tool for individual data (https://nutshell-tool.com/).

Complications of external cerebrospinal fluid drainage in aneurysmal subarachnoid haemorrhage.

BACKGROUND: The need for external cerebrospinal fluid (CSF) drains in aneurysmal subarachnoid haemorrhage (aSAH) patients is common and might lead to additional complications. OBJECTIVE: A relation between the presence of an external CSF drain and complication risk is investigated. METHODS: A prospective complication registry was analysed retrospectively. We included all adult aSAH patients admitted to our academic hospital between January 2016 and January 2018, treated with an external CSF drain. Demographic data, type of external drain used, the severity of the aSAH and complications, up to 30 days after drain placement, were registered. Complications were divided into (1) complications with a direct relation to the external CSF drain and (2) complications that could not be directly related to the use of an external CSF drain referred to as medical complications RESULTS: One hundred and forty drains were implanted in 100 aSAH patients. In total, 112 complications occurred in 59 patients. Thirty-six complications were drain related and 76 were medical complications. The most common complication was infection (n = 34). Drain dislodgement occurred 16 times, followed by meningitis (n = 11) and occlusion (n = 9). A Poisson model showed that the mean number of complications raised by 2.9% for each additional day of drainage (95% CI: 0.6-5.3% p = 0.01). CONCLUSION: Complications are common in patients with aneurysmal subarachnoid haemorrhage of which 32% are drain-related. A correlation is present between drainage period and the number of complications. Therefore, reducing drainage period could be a target for further improvement of care.

Iron chelators for acute stroke.

BACKGROUND: Stroke is the second leading cause of death and a major cause of morbidity worldwide. Retrospective clinical and animal studies have demonstrated neuroprotective effects of iron chelators in people with haemorrhagic or ischaemic stroke. This is the first update of the original Cochrane Review published in 2012. OBJECTIVES: To evaluate the effectiveness and safety of iron-chelating drugs in people with acute stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (2 September 2019), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2019, Issue 9; 2 September 2019), MEDLINE Ovid (2 September 2019), Embase Ovid (2 September 2019), and Science Citation Index (2 September 2019). We also searched ongoing trials registers. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of iron chelators versus no iron chelators or placebo for the treatment of acute stroke, including subarachnoid haemorrhage. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results. We obtained the full texts of potentially relevant studies and evaluated them for eligibility. We assessed risk of bias using the Cochrane 'Risk of bias' tool, and the certainty of evidence using the GRADE approach. MAIN RESULTS: Two RCTs (333 participants) were eligible for inclusion; both compared the iron-chelating agent deferoxamine against placebo. Both studies evaluated participants with spontaneous intracerebral haemorrhage. We assessed one study to have a low risk of bias; the other study had potential sources of bias. The limited and heterogeneous data did not allow for meta-analysis of the outcome parameters. The evidence suggests that administration of deferoxamine may result in little to no difference in deaths (8% in placebo vs 8% in deferoxamine at 180 days; 1 RCT, 291 participants; low-certainty evidence). These RCTs suggest that there may be little to no difference in good functional outcome (modified Rankin Scale score 0 to 2) between groups at 30, 90 and 180 days (placebo vs deferoxamine: 67% vs 57% at 30 days and 36% vs 45% at 180 days; 2 RCTs, 333 participants; low-certainty evidence). One RCT suggests that administration of deferoxamine may not increase the number of serious adverse events or deaths (placebo vs deferoxamine: 33% vs 27% at 180 days; risk ratio 0.81, 95 % confidence interval 0.57 to 1.16; 1 RCT, 291 participants; low-certainty evidence). No data were available on any deaths within the treatment period. Deferoxamine may result in little to no difference in the evolution of National Institute of Health Stroke Scale scores from baseline to 90 days (placebo vs deferoxamine: 13 to 4 vs 13 to 3; P = 0.37; 2 RCTs, 333 participants; low-certainty evidence). Deferoxamine may slightly reduce relative oedema surrounding intracerebral haemorrhage at 15 days (placebo vs deferoxamine: 1.91 vs 10.26; P = 0.042; 2 RCTs, 333 participants; low-certainty evidence). Neither study reported quality of life. AUTHORS' CONCLUSIONS: We identified two eligible RCTs for assessment. We could not demonstrate any benefit for the use of iron chelators in spontaneous intracerebral haemorrhage. The added value of iron-chelating therapy in people with ischaemic stroke or subarachnoid haemorrhage remains unknown.

Combining deep learning with 3D stereophotogrammetry for craniosynostosis diagnosis.

Craniosynostosis is a condition in which cranial sutures fuse prematurely, causing problems in normal brain and skull growth in infants. To limit the extent of cosmetic and functional problems, swift diagnosis is needed. The goal of this study is to investigate if a deep learning algorithm is capable of correctly classifying the head shape of infants as either healthy controls, or as one of the following three craniosynostosis subtypes; scaphocephaly, trigonocephaly or anterior plagiocephaly. In order to acquire cranial shape data, 3D stereophotographs were made during routine pre-operative appointments of scaphocephaly (n = 76), trigonocephaly (n = 40) and anterior plagiocephaly (n = 27) patients. 3D Stereophotographs of healthy infants (n = 53) were made between the age of 3-6 months. The cranial shape data was sampled and a deep learning network was used to classify the cranial shape data as either: healthy control, scaphocephaly patient, trigonocephaly patient or anterior plagiocephaly patient. For the training and testing of the deep learning network, a stratified tenfold cross validation was used. During testing 195 out of 196 3D stereophotographs (99.5%) were correctly classified. This study shows that trained deep learning algorithms, based on 3D stereophotographs, can discriminate between craniosynostosis subtypes and healthy controls with high accuracy.

Elevation of inflammatory S100A8/S100A9 complexes in intracranial aneurysms.

BACKGROUND: Inflammation-related factors might give further insight into the pathophysiology of vessel wall inflammation and intracranial aneurysm (IA) rupture. One of these factors is the protein complex S100A8/A9, which is released by neutrophils, monocytes, and activated macrophages and is known for its role in cardiovascular disease. OBJECTIVE: To determine if venous S100A8/A9 levels in patients with a ruptured IA (rIA) or unruptured IA (uIA) are elevated compared with a control group. Second, to assess differences between venous and intra-aneurysmal S100A8/A9 levels of rIA and uIA patients. METHODS: A prospective case study was performed between June 2016 and May 2017 in patients harboring a ruptured or unruptured saccular IA. Primary outcome measures were individual S100A8/A9 serum concentrations as measured in venous and intra-aneurysmal blood samples during endovascular treatment. Venous serum S100A8/A9 concentrations from a healthy control group served as a reference. RESULTS: We included 16 patients with either a rIA or uIA and 47 healthy controls. Venous S100A8/A9 concentrations were higher in aneurysm patients (rIA and uIA) than those of healthy controls (P≤0.001). S100A8/A9 concentrations were higher in intra-aneurysmal samples than in venous samples of rIA patients (P=0.011). This difference was not found in uIA patients (P=0.054). Intra-aneurysmal S100A8/A9 levels were higher in rIAs than in uIAs (P=0.04). CONCLUSIONS: Venous S100A8/A9 levels are elevated in patients with both rIAs and uIAs compared with healthy controls and likely represents aneurysm wall inflammation. S100A8/A9 causes macrophage-induced inflammation and degeneration of the vessel wall which might explain higher intra-aneurysmal S100A8/A9 levels found in rIAs than in uIAs.

Flow diversion treatment for acutely ruptured aneurysms.

BACKGROUND AND PURPOSE: Flow diverters are sometimes used in the setting of acutely ruptured aneurysms. However, thromboembolic and hemorrhagic complications are feared and evidence regarding safety is limited. Therefore, in this multicenter study we evaluated complications, clinical, and angiographic outcomes of patients treated with a flow diverter for acutely ruptured aneurysms. METHODS: We conducted a retrospective observational study of 44 consecutive patients who underwent flow diverter treatment within 15 days after rupture of an intracranial aneurysm at six centers. The primary end point was good clinical outcome, defined as modified Rankin Scale score (mRS) 0-2. Secondary endpoints were procedure-related complications and complete aneurysm occlusion at follow-up. RESULTS: At follow-up (median 3.4 months) 20 patients (45%) had a good clinical outcome. In 20 patients (45%), 25 procedure-related complications occurred. These resulted in permanent neurologic deficits in 12 patients (27%). In 5 patients (11%) aneurysm re-rupture occurred. Eight patients died resulting in an all-cause mortality rate of 18%. Procedure-related complications were associated with a poor clinical outcome (mRS 3-6; OR 5.1(95% CI 1.0 to 24.9), p=0.04). Large aneurysms were prone to re-rupture with rebleed rates of 60% (3/5) vs 5% (2/39) (p=0.01) for aneurysms with a size ≥20 mm and <20 mm, respectively. Follow-up angiography in 29 patients (median 9.7 months) showed complete aneurysm occlusion in 27 (93%). CONCLUSION: Flow diverter treatment of ruptured intracranial aneurysms was associated with high rates of procedure-related complications including aneurysm re-ruptures. Complications were associated with poor clinical outcome. In patients with available angiographic follow-up, a high occlusion rate was observed.

The Importance of Wall Apposition in Flow Diverters.

BACKGROUND: It is assumed that high pore densities in flow diverters (FDs) are beneficial for intracranial aneurysm (IA) healing. However, various animal studies are not conclusive on the issue, suggesting that other factors are in play. One important factor might be wall apposition. OBJECTIVE: To (1) determine the relationship between FD pore density and aneurysm occlusion, and (2) determine the relationship between FD wall apposition and aneurysm occlusion. METHODS: Saccular aneurysms were microsurgically created in the aorta of 36 Wistar rats. Twelve rats received a low pore density FD (10 pores/mm2), 12 rats received a high pore density FD (23 pores/mm2), and the remaining 12 rats served as a control group. Six animals from each group were sacrificed 1 and 3 mo after surgery. We determined aneurysm occlusion, the number of struts not in contact with the aorta wall, and the average distance from malapposed struts to aorta wall through histology. RESULTS: No significant differences were found in aneurysm occlusion between the low pore density and high pore density groups (P > .05) after 1 and 3 mo of follow-up. The average number of malapposed struts was lower for the occluded aneurysm group (4.4 ± 1.9) compared to the nonoccluded aneurysm group (7.7 ± 2.6, P < .01). The average distance between malapposed struts and parent artery wall was lower for the occluded aneurysm group (33.9 µm ± 11.5 µm) than for the nonoccluded aneurysm group (48.7 µm ± 18.8 µm, P < .05). CONCLUSION: Wall apposition is more important than pore density for aneurysm occlusion.