A national surveillance system for continuous monitoring of blood transfusion safety: German haemovigilance data.

BACKGROUND AND OBJECTIVES: Haemovigilance (HV) systems aim to improve transfusion outcomes in patients and donor safety. An important question for blood regulators is how to ensure an effective HV system. MATERIALS AND METHODS: We retrospectively analysed the HV reports submitted to Paul-Ehrlich-Institut over the last two decades. RESULTS: Between 2011 and 2020, 50.86 million units of blood components were used, and 8931 suspected serious donor and recipient adverse reactions (SARs), 874 serious adverse events (SAEs) and 12,073 donor look-backs were reported. Following implementation of specific risk-minimization measures (RMMs) between 2000 and 2010, SAR reporting rates decreased for transfusion-transmitted viral infections (TTVIs), transfusion-related acute lung injury (TRALI) and transfusion-transmitted bacterial infections (TTBIs), while increasing for other serious adverse transfusion reactions. Within this decade, the overall blood component use decreased. CONCLUSION: Long-term data collection forms the basis to establish trends and changes in reporting and to evaluate the effect of RMM. Standardized criteria for reaction types, seriousness and imputability assessments and availability of a denominator are important elements. Central data collection and independent assessment allow for monitoring HV data in a nationwide context over time. Stakeholder involvement and transparent feedback on the benefit of RMM will help to achieve the objectives of HV.

Regulatory Measures to Improve the Safety of CAR-T-Cell Treatment.

Introduction: Regulatory activities aim to facilitate the safe use of novel therapeutics such as genetically engineered chimeric antigen receptor (CAR)-T cells. Toxicities associated with CAR-T-cell therapies have led to modified safety management guidance in clinical trials and the implementation of post-marketing requirements. The aim of this study was to estimate the effect of individual risk-minimizing measures to evaluate the appropriateness of regulatory activities. Methods: We re-examined clinical trial data prior to and after the introduction of revised treatment guidelines; we analysed spontaneous adverse drug reaction (ADR) reports submitted to the EudraVigilance database in 2019/2020 regarding their completeness; and we performed a survey of treatment centres in Germany that have been qualified for the use of commercial CAR-T cells. Results: Lower combined incidences of severe cytokine release syndrome (CRS) as well as neurotoxicity occurred following CAR-T-cell treatment after a revision of management guidelines, suggesting earlier intervention compared to before (12.6% vs. 20.5%). Numerous post-marketing ADR reports lacked information important for case assessment. Full details on treatment indication, CRS onset, outcome, and grading were available for just 38.3% of CRS cases. Survey responses support the majority of regulatory requirements for centre qualification. Time investment was highest for training of healthcare professionals, which required an average of 6.5 staff members (range 2-20) and lasted more than 2 days per person in half of the facilities. The need to harmonize the regulatory requirements for the different CAR-T-cell therapeutics was emphasized. Conclusion: Defined regulatory measures can support the safe and effective use of new therapies and are indicated for structured recording of post-marketing data, and the evaluation of such measures appears to be necessary for the continuous improvement.

Pseudo-Enhancement in Intracranial Aneurysms on Black-Blood MRI: Effects of Flow Rate, Spatial Resolution, and Additional Flow Suppression.

BACKGROUND: Vessel-wall enhancement (VWE) on black-blood MRI (BB MRI) has been proposed as an imaging marker for a higher risk of rupture and associated with wall inflammation. Whether VWE is causally linked to inflammation or rather induced by flow phenomena has been a subject of debate. PURPOSE: To study the effects of slow flow, spatial resolution, and motion-sensitized driven equilibrium (MSDE) preparation on signal intensities in BB MRI of patient-specific aneurysm flow models. STUDY TYPE: Prospective. SUBJECTS/FLOW ANEURYSM MODEL/VIRTUAL VESSELS: Aneurysm flow models based on 3D rotational angiography datasets of three patients with intracranial aneurysms were 3D printed and perfused at two different flow rates, with and without Gd-containing contrast agent. FIELD STRENGTH/SEQUENCE: Variable refocusing flip angle 3D fast-spin echo sequence at 3 T with and without MSDE with three voxel sizes ((0.5 mm)3 , (0.7 mm)3 , and (0.9 mm)3 ); time-resolved with phase-contrast velocity-encoding 3D spoiled gradient echo sequence (4D flow MRI). ASSESSMENT: Three independent observers performed a qualitative visual assessment of flow patterns and signal enhancement. Quantitative analysis included voxel-wise evaluation of signal intensities and magnitude velocity distributions in the aneurysm. STATISTICAL TESTS: Kruskal-Wallis test, potential regressions. RESULTS: A hyperintense signal in the lumen and adjacent to the aneurysm walls on BB MRI was colocalized with slow flow. Signal intensities increased by a factor of 2.56 ± 0.68 (P < 0.01) after administering Gd contrast. After Gd contrast administration, the signal was suppressed most in conjunction with high flows and with MSDE (2.41 ± 2.07 for slow flow without MSDE, and 0.87 ± 0.99 for high flow with MSDE). A clear result was not achieved by modifying the spatial resolution . DATA CONCLUSIONS: Slow-flow phenomena contribute substantially to aneurysm enhancement and vary with MRI parameters. This should be considered in the clinical setting when assessing VWE in patients with an unruptured aneurysm. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Multimodal validation of focal enhancement in intracranial aneurysms as a surrogate marker for aneurysm instability.

PURPOSE: Circumferential enhancement on MR vessel wall imaging has been proposed as a biomarker of a higher risk of rupture in intracranial aneurysms. Focal enhancement is frequently encountered in unruptured aneurysms, but its implication for risk stratification and patient management remains unclear. This study investigates the association of focal wall enhancement with hemodynamic and morphological risk factors and histologic markers of wall inflammation and degeneration. METHODS: Patients with an unruptured middle cerebral artery aneurysm who underwent 3D rotational angiography and 3T MR vessel wall imaging showing focal wall enhancement were included. Hemodynamic parameters were calculated based on flow simulations and compared between enhanced regions and the entire aneurysm surface. Morphological parameters were semiautomatically extracted and quantitatively associated with wall enhancement. Histological analysis included detection of vasa vasorum, CD34, and myeloperoxidase staining in a subset of patients. RESULTS: Twenty-two aneurysms were analyzed. Enhanced regions were significantly associated with lower AWSS, lower maxOSI, and increased LSA. In multivariate analysis, higher ellipticity index was an independent predictor of wall enhancement. Histologic signs of inflammation and degeneration and higher PHASES score were significantly associated with focal enhancement. CONCLUSION: Focal wall enhancement is colocalized with hemodynamic factors that have been related to a higher rupture risk. It is correlated with morphological factors linked to rupture risk, higher PHASES score, and histologic markers of wall destabilization. The results support the hypothesis that focal enhancement could serve as a surrogate marker for aneurysm instability.

Multiple Aneurysms AnaTomy CHallenge 2018 (MATCH): uncertainty quantification of geometric rupture risk parameters.

BACKGROUND: Geometric parameters have been proposed for prediction of cerebral aneurysm rupture risk. Predicting the rupture risk for incidentally detected unruptured aneurysms could help clinicians in their treatment decision. However, assessment of geometric parameters depends on several factors, including the spatial resolution of the imaging modality used and the chosen reconstruction procedure. The aim of this study was to investigate the uncertainty of a variety of previously proposed geometric parameters for rupture risk assessment, caused by variability of reconstruction procedures. MATERIALS: 26 research groups provided segmentations and surface reconstructions of five cerebral aneurysms as part of the Multiple Aneurysms AnaTomy CHallenge (MATCH) 2018. 40 dimensional and non-dimensional geometric parameters, describing aneurysm size, neck size, and irregularity of aneurysm shape, were computed. The medians as well as the absolute and relative uncertainties of the parameters were calculated. Additionally, linear regression analysis was performed on the absolute uncertainties and the median parameter values. RESULTS: A large variability of relative uncertainties in the range between 3.9 and 179.8% was found. Linear regression analysis indicates that some parameters capture similar geometric aspects. The lowest uncertainties < 6% were found for the non-dimensional parameters isoperimetric ratio, convexity ratio, and ellipticity index. Uncertainty of 2D and 3D size parameters was significantly higher than uncertainty of 1D parameters. The most extreme uncertainties > 80% were found for some curvature parameters. CONCLUSIONS: Uncertainty analysis is essential on the road to clinical translation and use of rupture risk prediction models. Uncertainty quantification of geometric rupture risk parameters provided by this study may help support development of future rupture risk prediction models.

Evaluation of flow changes after telescopic stenting of a giant fusiform aneurysm of the vertebrobasilar junction.

BACKGROUND: The use of flow-diverters for non-saccular cerebral posterior circulation aneurysms requires complex deployment techniques and is associated with high mortality and morbidity. Therefore, further studies are required to clarify the effect of stenting on post-treatment hemodynamics in such aneurysms. In this study, we evaluated flow alterations in a treated giant fusiform aneurysm of the vertebrobasilar junction and correlated them with the clinical outcome. METHODS: A patient-specific aneurysm model was acquired by rotational angiography, and three SILK flow-diverters (4.5 × 40, 5 × 40 and 5.5 × 40 mm) were virtually deployed in series along the basilar and right vertebral arteries. Image-based blood flow simulations before and after the treatment were performed under realistic pulsatile flow conditions. The flow reduction, velocity and wall shear stress (WSS) distribution, streamlines and WSS-derived parameters were evaluated before and after the treatment. RESULTS: The computed velocity streamlines showed substantial alterations of the flow pattern in the aneurysm and successful redirection of blood flow along the series of flow-diverters with no flow through the overlapping stents. The obtained flow reduction of 86% was sufficient to create thrombogenic flow conditions. Moreover, a 6.2-fold increase in relative residence time and a decrease by 87% of time-averaged WSS contributed to a successful treatment outcome observed during the follow-up. CONCLUSIONS: We found a correlation between the numerically predicted flow alterations and the available treatment outcome. This shows the potential of image-based simulations to be used in clinical practice for treatment planning and estimation of possible risk factors associated with a complex stent deployment in fusiform aneurysms of the posterior circulation.

A review on the reliability of hemodynamic modeling in intracranial aneurysms: why computational fluid dynamics alone cannot solve the equation.

Computational blood flow modeling in intracranial aneurysms (IAs) has enormous potential for the assessment of highly resolved hemodynamics and derived wall stresses. This results in an improved knowledge in important research fields, such as rupture risk assessment and treatment optimization. However, due to the requirement of assumptions and simplifications, its applicability in a clinical context remains limited.This review article focuses on the main aspects along the interdisciplinary modeling chain and highlights the circumstance that computational fluid dynamics (CFD) simulations are embedded in a multiprocess workflow. These aspects include imaging-related steps, the setup of realistic hemodynamic simulations, and the analysis of multidimensional computational results. To condense the broad knowledge, specific recommendations are provided at the end of each subsection.Overall, various individual substudies exist in the literature that have evaluated relevant technical aspects. In this regard, the importance of precise vessel segmentations for the simulation outcome is emphasized. Furthermore, the accuracy of the computational model strongly depends on the specific research question. Additionally, standardization in the context of flow analysis is required to enable an objective comparison of research findings and to avoid confusion within the medical community. Finally, uncertainty quantification and validation studies should always accompany numerical investigations.In conclusion, this review aims for an improved awareness among physicians regarding potential sources of error in hemodynamic modeling for IAs. Although CFD is a powerful methodology, it cannot provide reliable information, if pre- and postsimulation steps are inaccurately carried out. From this, future studies can be critically evaluated and real benefits can be differentiated from results that have been acquired based on technically inaccurate procedures.

The Computational Fluid Dynamics Rupture Challenge 2013--Phase II: Variability of Hemodynamic Simulations in Two Intracranial Aneurysms.

With the increased availability of computational resources, the past decade has seen a rise in the use of computational fluid dynamics (CFD) for medical applications. There has been an increase in the application of CFD to attempt to predict the rupture of intracranial aneurysms, however, while many hemodynamic parameters can be obtained from these computations, to date, no consistent methodology for the prediction of the rupture has been identified. One particular challenge to CFD is that many factors contribute to its accuracy; the mesh resolution and spatial/temporal discretization can alone contribute to a variation in accuracy. This failure to identify the importance of these factors and identify a methodology for the prediction of ruptures has limited the acceptance of CFD among physicians for rupture prediction. The International CFD Rupture Challenge 2013 seeks to comment on the sensitivity of these various CFD assumptions to predict the rupture by undertaking a comparison of the rupture and blood-flow predictions from a wide range of independent participants utilizing a range of CFD approaches. Twenty-six groups from 15 countries took part in the challenge. Participants were provided with surface models of two intracranial aneurysms and asked to carry out the corresponding hemodynamics simulations, free to choose their own mesh, solver, and temporal discretization. They were requested to submit velocity and pressure predictions along the centerline and on specified planes. The first phase of the challenge, described in a separate paper, was aimed at predicting which of the two aneurysms had previously ruptured and where the rupture site was located. The second phase, described in this paper, aims to assess the variability of the solutions and the sensitivity to the modeling assumptions. Participants were free to choose boundary conditions in the first phase, whereas they were prescribed in the second phase but all other CFD modeling parameters were not prescribed. In order to compare the computational results of one representative group with experimental results, steady-flow measurements using particle image velocimetry (PIV) were carried out in a silicone model of one of the provided aneurysms. Approximately 80% of the participating groups generated similar results. Both velocity and pressure computations were in good agreement with each other for cycle-averaged and peak-systolic predictions. Most apparent "outliers" (results that stand out of the collective) were observed to have underestimated velocity levels compared to the majority of solutions, but nevertheless identified comparable flow structures. In only two cases, the results deviate by over 35% from the mean solution of all the participants. Results of steady CFD simulations of the representative group and PIV experiments were in good agreement. The study demonstrated that while a range of numerical schemes, mesh resolution, and solvers was used, similar flow predictions were observed in the majority of cases. To further validate the computational results, it is suggested that time-dependent measurements should be conducted in the future. However, it is recognized that this study does not include the biological aspects of the aneurysm, which needs to be considered to be able to more precisely identify the specific rupture risk of an intracranial aneurysm.

Cerebral blood flow in a healthy Circle of Willis and two intracranial aneurysms: computational fluid dynamics versus four-dimensional phase-contrast magnetic resonance imaging.

Computational fluid dynamics (CFD) opens up multiple opportunities to investigate the hemodynamics of the human vascular system. However, due to numerous assumptions the acceptance of CFD among physicians is still limited in practice and validation through comparison is mandatory. Time-dependent quantitative phase-contrast magnetic resonance imaging PC-MRI measurements in a healthy volunteer and two intracranial aneurysms were carried out at 3 and 7 Tesla. Based on the acquired images, three-dimensional (3D) models of the aneurysms were reconstructed and used for the numerical simulations. Flow information from the MR measurements were applied as boundary conditions. The four-dimensional (4D) velocity fields obtained by CFD and MRI were qualitatively as well as quantitatively compared including cut planes and vector analyses. For all cases a high similarity of the velocity patterns was observed. Additionally, the quantitative analysis revealed a good agreement between CFD and MRI. Deviations were caused by minor differences between the reconstructed vessel models and the actual lumen. The comparisons between diastole and systole indicate that relative differences between MRI and CFD are intensified with increasing velocity. The findings of this study lead to the conclusion that CFD and MRI agree well in predicting intracranial velocities when realistic geometries and boundary conditions are provided. Due to the considerably higher temporal and spatial resolution of CFD compared to MRI, complex flow patterns can be further investigated in order to evaluate their role with respect to aneurysm formation or rupture. Nevertheless, special care is required regarding the vessel reconstruction since the geometry has a major impact on the subsequent numerical results.

Multi-Dimensional Modeling of Cerebral Hemodynamics: A Systematic Review.

The Circle of Willis (CoW) describes the arterial system in the human brain enabling the neurovascular blood supply. Neurovascular diseases like intracranial aneurysms (IAs) can occur within the CoW and carry the risk of rupture, which can lead to subarachnoid hemorrhage. The assessment of hemodynamic information in these pathologies is crucial for their understanding regarding detection, diagnosis and treatment. Multi-dimensional in silico approaches exist to evaluate these hemodynamics based on patient-specific input data. The approaches comprise low-scale (zero-dimensional, one-dimensional) and high-scale (three-dimensional) models as well as multi-scale coupled models. The input data can be derived from medical imaging, numerical models, literature-based assumptions or from measurements within healthy subjects. Thus, the most realistic description of neurovascular hemodynamics is still controversial. Within this systematic review, first, the models of the three scales (0D, 1D, 3D) and second, the multi-scale models, which are coupled versions of the three scales, were discussed. Current best practices in describing neurovascular hemodynamics most realistically and their clinical applicablility were elucidated. The performance of 3D simulation entails high computational expenses, which could be reduced by analyzing solely the region of interest in detail. Medical imaging to establish patient-specific boundary conditions is usually rare, and thus, lower dimensional models provide a realistic mimicking of the surrounding hemodynamics. Multi-scale coupling, however, is computationally expensive as well, especially when taking all dimensions into account. In conclusion, the 0D-1D-3D multi-scale approach provides the most realistic outcome; nevertheless, it is least applicable. A 1D-3D multi-scale model can be considered regarding a beneficial trade-off between realistic results and applicable performance.

A confirmed human fatality due to envenomation by the Kunene Coral Snake (Aspidelaps lubricus cowlesi) in Namibia.

Shield-nose and Coral snakes (Aspidelaps spp.) are medium sized venomous snakes found throughout southern Africa. Little is known about the venom of these snakes and its clinical relevance, as human bites are uncommon. Neurological signs and symptoms usually develop following bites by this genus but evaluations of the severity are inconclusive. We report on the first confirmed human fatality by the Kunene Shield-nose Snake (Aspidelaps lubricus cowlesi) in a child. Envenomation by Aspidelaps and other snakes considered lesser-venomous - especially those possessing neurotoxic venom - should be treated with caution as they may result in life-threatening envenomation without established clinical management protocols.

Image-based hemodynamic simulations for intracranial aneurysms: the impact of complex vasculature.

PURPOSE: Hemodynamics play an important role in the assessment of intracranial aneurysm (IA) development and rupture risk. The purpose of this study was to examine the impact of complex vasculatures onto the intra-vessel and intra-aneurysmal blood flow. METHODS: Complex segmentation of a subject-specific, 60-outlet and 3-inlet circle of Willis model captured with 7T magnetic resonance imaging was performed. This model was trimmed to a 10-outlet model version. Two patient-specific IAs were added onto both models yielding two pathological versions, and image-based blood flow simulations of the four resulting cases were carried out. To capture the differences between complex and trimmed model, time-averaged and centerline velocities were compared. The assessment of intra-saccular blood flow within the IAs involved the evaluation of wall shear stresses (WSS) at the IA wall and neck inflow rates (NIR). RESULTS: Lower flow values are observed in the majority of the complex model. However, at specific locations (left middle cerebral artery 0.5 m/s, left posterior cerebral artery 0.25 m/s), higher flow rates were visible when compared to the trimmed counterpart. Furthermore, at the centerlines the total velocity values reveal differences up to 0.15 m/s. In the IAs, the reduction in the neck inflow rate and WSS in the complex model was observed for the first IA (IA-A δNIRmean = - 0.07ml/s, PCA.l δWSSmean = - 0.05 Pa). The second IA featured an increase in the neck inflow rate and WSS (IA-B δNIRmean = 0.04 ml/s, PCA.l δWSSmean = 0.07 Pa). CONCLUSION: Both the magnitude and shape of the flow distribution vary depending on the model's complexity. The magnitude is primarily influenced by the global vessel model, while the shape is determined by the local structure. Furthermore, intra-aneurysmal flow strongly depends on the location in the vessel tree, emphasizing the need for complex model geometries for realistic hemodynamic assessment and rupture risk analysis.

Fusiform versus Saccular Intracranial Aneurysms-Hemodynamic Evaluation of the Pre-Aneurysmal, Pathological, and Post-Interventional State.

Minimally-invasive therapies are well-established treatment methods for saccular intracranial aneurysms (SIAs). Knowledge concerning fusiform IAs (FIAs) is low, due to their wide and alternating lumen and their infrequent occurrence. However, FIAs carry risks like ischemia and thus require further in-depth investigation. Six patient-specific IAs, comprising three position-identical FIAs and SIAs, with the FIAs showing a non-typical FIA shape, were compared, respectively. For each model, a healthy counterpart and a treated version with a flow diverting stent were created. Eighteen time-dependent simulations were performed to analyze morphological and hemodynamic parameters focusing on the treatment effect (TE). The stent expansion is higher for FIAs than SIAs. For FIAs, the reduction in vorticity is higher (Δ35-75% case 2/3) and the reduction in the oscillatory velocity index is lower (Δ15-68% case 2/3). Velocity is reduced equally for FIAs and SIAs with a TE of 37-60% in FIAs and of 41-72% in SIAs. Time-averaged wall shear stress (TAWSS) is less reduced within FIAs than SIAs (Δ30-105%). Within this study, the positive TE of FDS deployed in FIAs is shown and a similarity in parameters found due to the non-typical FIA shape. Despite the higher stent expansion, velocity and vorticity are equally reduced compared to identically located SIAs.

Are hemodynamics responsible for inflammatory changes in venous vessel walls? A quantitative study of wall-enhancing intracranial arteriovenous malformation draining veins.

OBJECTIVE: Signal enhancement of vascular walls on vessel wall MRI might be a biomarker for inflammation. It has been theorized that contrast enhancement on vessel wall imaging (VWI) in draining veins of intracranial arteriovenous malformations (AVMs) may be associated with disease progression and development of venous stenosis. The aim of this study was to investigate the relationship between vessel wall enhancement and hemodynamic stressors along AVM draining veins. METHODS: Eight AVM patients with 15 draining veins visualized on VWI were included. Based on MR venography data, patient-specific 3D surface models of the venous anatomy distal to the nidus were segmented. The enhanced vascular wall regions were manually extracted and mapped onto the venous surface models after registration of image data. Using image-based blood flow simulations applying patient-specific boundary conditions based on phase-contrast quantitative MR angiography, hemodynamics were investigated in the enhanced vasculature. For the shear-related parameters, time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), and relative residence time (RRT) were calculated. Velocity, oscillatory velocity index (OVI), and vorticity were extracted for the intraluminal flow-related hemodynamics. RESULTS: Visual observations demonstrated overlap of enhancement with local lower shear stresses resulting from decreased velocities. Thus, higher RRT values were measured in the enhanced areas. Furthermore, nonenhancing draining veins showed on average slightly higher flow velocities and TAWSS. Significant decreases of 55% (p = 0.03) for TAWSS and of 24% (p = 0.03) for vorticity were identified in enhanced areas compared with near distal and proximal domains. Velocity magnitude in the enhanced region showed a nonsignificant decrease of 14% (p = 0.06). Furthermore, increases were present in the OSI (32%, p = 0.3), RRT (25%, p = 0.15), and OVI (26%, p = 0.3) in enhanced vessel sections, although the differences were not significant. CONCLUSIONS: This novel multimodal investigation of hemodynamics in AVM draining veins allows for precise prediction of occurring shear- and flow-related phenomena in enhanced vessel walls. These findings may suggest low shear to be a local predisposing factor for venous stenosis in AVMs.

Variability of computational fluid dynamics solutions for pressure and flow in a giant aneurysm: the ASME 2012 Summer Bioengineering Conference CFD Challenge.

Stimulated by a recent controversy regarding pressure drops predicted in a giant aneurysm with a proximal stenosis, the present study sought to assess variability in the prediction of pressures and flow by a wide variety of research groups. In phase I, lumen geometry, flow rates, and fluid properties were specified, leaving each research group to choose their solver, discretization, and solution strategies. Variability was assessed by having each group interpolate their results onto a standardized mesh and centerline. For phase II, a physical model of the geometry was constructed, from which pressure and flow rates were measured. Groups repeated their simulations using a geometry reconstructed from a micro-computed tomography (CT) scan of the physical model with the measured flow rates and fluid properties. Phase I results from 25 groups demonstrated remarkable consistency in the pressure patterns, with the majority predicting peak systolic pressure drops within 8% of each other. Aneurysm sac flow patterns were more variable with only a few groups reporting peak systolic flow instabilities owing to their use of high temporal resolutions. Variability for phase II was comparable, and the median predicted pressure drops were within a few millimeters of mercury of the measured values but only after accounting for submillimeter errors in the reconstruction of the life-sized flow model from micro-CT. In summary, pressure can be predicted with consistency by CFD across a wide range of solvers and solution strategies, but this may not hold true for specific flow patterns or derived quantities. Future challenges are needed and should focus on hemodynamic quantities thought to be of clinical interest.

Multimodal exploration of the intracranial aneurysm wall.

PURPOSE: Intracranial aneurysms (IAs) are pathological changes of the intracranial vessel wall, although clinical image data can only show the vessel lumen. Histology can provide wall information but is typically restricted to ex vivo 2D slices where the shape of the tissue is altered. METHODS: We developed a visual exploration pipeline for a comprehensive view of an IA. We extract multimodal information (like stain classification and segmentation of histologic images) and combine them via 2D to 3D mapping and virtual inflation of deformed tissue. Histological data, including four stains, micro-CT data and segmented calcifications as well as hemodynamic information like wall shear stress (WSS), are combined with the 3D model of the resected aneurysm. RESULTS: Calcifications were mostly present in the tissue part with increased WSS. In the 3D model, an area of increased wall thickness was identified and correlated to histology, where the Oil red O (ORO) stained images showed a lipid accumulation and the alpha-smooth muscle actin (aSMA) stained images showed a slight loss of muscle cells. CONCLUSION: Our visual exploration pipeline combines multimodal information about the aneurysm wall to improve the understanding of wall changes and IA development. The user can identify regions and correlate how hemodynamic forces, e.g. WSS, are reflected by histological structures of the vessel wall, wall thickness and calcifications.

Assessment of the flow-diverter efficacy for intracranial aneurysm treatment considering pre- and post-interventional hemodynamics.

Endovascular treatment of intracranial aneurysms with flow diverters (FD) has become one of the most promising interventions. Due to its woven high-density structure they are particularly applicable for challenging lesions. Although several studies have already conducted realistic hemodynamic quantification of the FD efficacy, a comparison with morphologic post-interventional data is still missing. This study analyses the hemodynamics of ten intracranial aneurysm patients treated with a novel FD device. Based on pre- and post-interventional 3D digital subtraction angiography image data, patient-specific 3D models of both treatment states are generated applying open source threshold-based segmentation methods. Using a fast virtual stenting approach, the real stent positions available in the post-interventional data are virtually replicated and both treatment scenarios were characterized using image-based blood flow simulations. The results show FD-induced flow reductions at the ostium by a decrease in mean neck flow rate (51%), inflow concentration index (56%) and mean inflow velocity (53%). Intraluminal reductions in flow activity for time-averaged wall shear stress (47%) and kinetic energy (71%) are present as well. However, an intra-aneurysmal increase in flow pulsatility (16%) for the post-interventional cases can be observed. Patient-specific FD simulations demonstrate the desired flow redirection and activity reduction inside the aneurysm beneficial for thrombosis formation. Differences in the magnitude of hemodynamic reduction exist over the cardiac cycle which may be addressed in a clinical setting by anti-hypertensive treatment in selected cases.

Is Accurate Lumen Segmentation More Important than Outlet Boundary Condition in Image-Based Blood Flow Simulations for Intracranial Aneurysms?

PURPOSE: Image-based blood flow simulations are increasingly used to investigate the hemodynamics in intracranial aneurysms (IAs). However, a strong variability in segmentation approaches as well as the absence of individualized boundary conditions (BCs) influence the quality of these simulation results leading to imprecision and decreased reliability. This study aims to analyze these influences on relevant hemodynamic parameters within IAs. METHODS: As a follow-up study of an international multiple aneurysms challenge, the segmentation results of five IAs differing in size and location were investigated. Specifically, five possible outlet BCs were considered in each of the IAs. These are comprised of the zero-pressure condition (BC1), a flow distribution based on Murray's law with the exponents n = 2 (BC2) and n = 3 (BC3) as well as two advanced flow-splitting models considering the real vessels by including circular cross sections (BC4) or anatomical cross sections (BC5), respectively. In total, 120 time-dependent blood flow simulations were analyzed qualitatively and quantitatively, focusing on five representative intra-aneurysmal flow and five shear parameters such as vorticity and wall shear stress. RESULTS: The outlet BC variation revealed substantial differences. Higher shear stresses (up to Δ9.69 Pa), intrasaccular velocities (up to Δ0.15 m/s) and vorticities (up to Δ629.22 1/s) were detected when advanced flow-splitting was applied compared to the widely used zero-pressure BC. The tendency of outlets BCs to over- or underestimate hemodynamic parameters is consistent across different segmentations of a single aneurysm model. Segmentation-induced variability reaches Δ19.58 Pa, Δ0.42 m/s and Δ957.27 1/s, respectively. Excluding low fidelity segmentations, however, (a) reduces the deviation drastically (>43%) and (b) leads to a lower impact of the outlet BC on hemodynamic predictions. CONCLUSION: With a more realistic lumen segmentation, the influence of the BC on the resulting hemodynamics is decreased. A realistic lumen segmentation can be ensured, e.g., by using high-resolved 2D images. Furthermore, the selection of an advanced outflow-splitting model is advised and the use of a zero-pressure BC and BC based on Murray's law with exponent n = 3 should be avoided.

In vitro and in silico assessment of flow modulation after deploying the Contour Neurovascular System in intracranial aneurysm models.

BACKGROUND: The novel Contour Neurovascular System (Contour) has been reported to be efficient and safe for the treatment of intracranial, wide-necked bifurcation aneurysms. Flow in the aneurysm and posterior cerebral arteries (PCAs) after Contour deployment has not been analyzed in detail yet. However, this information is crucial for predicting aneurysm treatment outcomes. METHODS: Time-resolved three-dimensional velocity maps in 14 combinations of patient-based basilar tip aneurysm models with and without Contour devices (sizes between 5 and 14 mm) were analyzed using four-dimensionsal (4D) flow MRI and numerical/image-based flow simulations. A complex virtual processing pipeline was developed to mimic the experimental shape and position of the Contour together with the simulations. RESULTS: On average, the Contour significantly reduced intra-aneurysmal flow velocity by 67% (mean w/ = 0.03m/s; mean w/o = 0.12m/s; p-value=0.002), and the time-averaged wall shear stress by more than 87% (mean w/ = 0.17Pa; mean w/o = 1.35Pa; p-value=0.002), as observed by numerical simulations. Furthermore, a significant reduction in flow (P<0.01) was confirmed by the neck inflow rate, kinetic energy, and inflow concentration index after Contour deployment. Notably, device size has a stronger effect on reducing flow than device positioning. However, positioning affected flow in the PCAs, while being robust in effectively reducing flow. CONCLUSIONS: This study showed the high efficacy of the Contour device in reducing flow within aneurysms regardless of the exact position. However, we observed an effect on the flow in PCAs, which needs to be investigated further.