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Felicitas J. Detmer, Sara Hadad, Bong Jae Chung, Fernando Mut, Martin Slawski, Norman Juchler, Vartan Kurtcuoglu, Sven Hirsch, Philippe Bijlenga, Yuya Uchiyama, Soichiro Fujimura, Makoto Yamamoto, Yuichi Murayama, Hiroyuki Takao, Timo Koivisto, Juhana Frösen and Juan R. Cebral

OBJECTIVE

Incidental aneurysms pose a challenge for physicians, who need to weigh the rupture risk against the risks associated with treatment and its complications. A statistical model could potentially support such treatment decisions. A recently developed aneurysm rupture probability model performed well in the US data used for model training and in data from two European cohorts for external validation. Because Japanese and Finnish patients are known to have a higher aneurysm rupture risk, the authors’ goals in the present study were to evaluate this model using data from Japanese and Finnish patients and to compare it with new models trained with Finnish and Japanese data.

METHODS

Patient and image data on 2129 aneurysms in 1472 patients were used. Of these aneurysm cases, 1631 had been collected mainly from US hospitals, 249 from European (other than Finnish) hospitals, 147 from Japanese hospitals, and 102 from Finnish hospitals. Computational fluid dynamics simulations and shape analyses were conducted to quantitatively characterize each aneurysm’s shape and hemodynamics. Next, the previously developed model’s discrimination was evaluated using the Finnish and Japanese data in terms of the area under the receiver operating characteristic curve (AUC). Models with and without interaction terms between patient population and aneurysm characteristics were trained and evaluated including data from all four cohorts obtained by repeatedly randomly splitting the data into training and test data.

RESULTS

The US model’s AUC was reduced to 0.70 and 0.72, respectively, in the Finnish and Japanese data compared to 0.82 and 0.86 in the European and US data. When training the model with Japanese and Finnish data, the average AUC increased only slightly for the Finnish sample (to 0.76 ± 0.16) and Finnish and Japanese cases combined (from 0.74 to 0.75 ± 0.14) and decreased for the Japanese data (to 0.66 ± 0.33). In models including interaction terms, the AUC in the Finnish and Japanese data combined increased significantly to 0.83 ± 0.10.

CONCLUSIONS

Developing an aneurysm rupture prediction model that applies to Japanese and Finnish aneurysms requires including data from these two cohorts for model training, as well as interaction terms between patient population and the other variables in the model. When including this information, the performance of such a model with Japanese and Finnish data is close to its performance with US or European data. These results suggest that population-specific differences determine how hemodynamics and shape associate with rupture risk in intracranial aneurysms.

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Georgios A. Zenonos, Samir Sur, Maximiliano Nuñez, David T. Fernandes-Cabral and Jacques J. Morcos

In this 3D video we review the case of a lower pontine cavernous malformation in a 31-year-old man who presented with hemiparesis and an abducens palsy. The cavernous malformation was completely resected through a far lateral approach and a peritrigeminal brainstem entry zone, with a significant improvement in the patient’s hemiparesis. The relevant anatomy is reviewed in detail through multiple anatomical brainstem dissection specimens, as well as high-definition fiber tractography images. The rationale for the approach is analyzed relative to other possible options, and a number of technical pearls are provided.

The video can be found here: https://youtu.be/fH2Q7RjlBKQ.

Free access

Juhana Frösen, Juan Cebral, Anne M. Robertson and Tomohiro Aoki

OBJECTIVE

Unruptured intracranial aneurysms (UIAs) are relatively common lesions that may cause devastating intracranial hemorrhage, thus producing considerable suffering and anxiety in those affected by the disease or an increased likelihood of developing it. Advances in the knowledge of the pathobiology behind intracranial aneurysm (IA) formation, progression, and rupture have led to preclinical testing of drug therapies that would prevent IA formation or progression. In parallel, novel biologically based diagnostic tools to estimate rupture risk are approaching clinical use. Arterial wall remodeling, triggered by flow and intramural stresses and mediated by inflammation, is relevant to both.

METHODS

This review discusses the basis of flow-driven vessel remodeling and translates that knowledge to the observations made on the mechanisms of IA initiation and progression on studies using animal models of induced IA formation, study of human IA tissue samples, and study of patient-derived computational fluid dynamics models.

RESULTS

Blood flow conditions leading to high wall shear stress (WSS) activate proinflammatory signaling in endothelial cells that recruits macrophages to the site exposed to high WSS, especially through macrophage chemoattractant protein 1 (MCP1). This macrophage infiltration leads to protease expression, which disrupts the internal elastic lamina and collagen matrix, leading to focal outward bulging of the wall and IA initiation. For the IA to grow, collagen remodeling and smooth muscle cell (SMC) proliferation are essential, because the fact that collagen does not distend much prevents the passive dilation of a focal weakness to a sizable IA. Chronic macrophage infiltration of the IA wall promotes this SMC-mediated growth and is a potential target for drug therapy. Once the IA wall grows, it is subjected to changes in wall tension and flow conditions as a result of the change in geometry and has to remodel accordingly to avoid rupture. Flow affects this remodeling process.

CONCLUSIONS

Flow triggers an inflammatory reaction that predisposes the arterial wall to IA initiation and growth and affects the associated remodeling of the UIA wall. This chronic inflammation is a putative target for drug therapy that would stabilize UIAs or prevent UIA formation. Moreover, once this coupling between IA wall remodeling and flow is understood, data from patient-specific flow models can be gathered as part of the diagnostic workup and utilized to improve risk assessment for UIA initiation, progression, and eventual rupture.

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Giulio Cecchini, Giovanni Vitale, Thomas J. Sorenson and Francesco Di Biase

Cavernous malformations in the midbrain can be accessed via several safe entry zones. The accepted rule of thumb is to enter at the point where the lesion is visible at the surface of the brainstem to pass through as little normal brain tissue as possible. However, in some cases, in order to avoid critical neural structures, this rule may not apply. A different safe entry zone can be chosen. Our video presents a case of a ruptured cavernous malformation in the midbrain reaching its anterior surface which was successfully resected via a posterolateral route using the supracerebellar infratentorial approach.

The video can be found here: https://youtu.be/j7VTqRO7qd4.

Free access

Nardin Samuel and Ivan Radovanovic

OBJECTIVE

Despite the prevalence and impact of intracranial aneurysms (IAs), the molecular basis of their pathogenesis remains largely unknown. Moreover, there is a dearth of clinically validated biomarkers to efficiently screen patients with IAs and prognosticate risk for rupture. The aim of this study was to survey the literature to systematically identify the spectrum of genetic aberrations that have been identified in IA formation and risk of rupture.

METHODS

A literature search was performed using the Medical Subject Headings (MeSH) system of databases including PubMed, EMBASE, and Google Scholar. Relevant studies that reported on genetic analyses of IAs, rupture risk, and long-term outcomes were included in the qualitative analysis.

RESULTS

A total of 114 studies were reviewed and 65 were included in the qualitative synthesis. There are several well-established mendelian syndromes that confer risk to IAs, with variable frequency. Linkage analyses, genome-wide association studies, candidate gene studies, and exome sequencing identify several recurrent polymorphic variants at candidate loci, and genes associated with the risk of aneurysm formation and rupture, including ANRIL (CDKN2B-AS1, 9p21), ARGHEF17 (11q13), ELN (7q11), SERPINA3 (14q32), and SOX17 (8q11). In addition, polymorphisms in eNOS/NOS3 (7q36) may serve as predictive markers for outcomes following intracranial aneurysm rupture. Genetic aberrations identified to date converge on posited molecular mechanisms involved in vascular remodeling, with strong implications for an associated immune-mediated inflammatory response.

CONCLUSIONS

Comprehensive studies of IA formation and rupture have identified candidate risk variants and loci; however, further genome-wide analyses are needed to identify high-confidence genetic aberrations. The literature supports a role for several risk loci in aneurysm formation and rupture with putative candidate genes. A thorough understanding of the genetic basis governing risk of IA development and the resultant aneurysmal subarachnoid hemorrhage may aid in screening, clinical management, and risk stratification of these patients, and it may also enable identification of putative mechanisms for future drug development.

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Mahsa Dabagh, Priya Nair, John Gounley, David Frakes, L. Fernando Gonzalez and Amanda Randles

The growth of cerebral aneurysms is linked to local hemodynamic conditions, but the driving mechanisms of the growth are poorly understood. The goal of this study was to examine the association between intraaneurysmal hemodynamic features and areas of aneurysm growth, to present the key hemodynamic parameters essential for an accurate prediction of the growth, and to gain a deeper understanding of the underlying mechanisms. Patient-specific images of a growing cerebral aneurysm in 3 different growth stages acquired over a period of 40 months were segmented and reconstructed. A unique aspect of this patient-specific case study was that while one side of the aneurysm stayed stable, the other side continued to grow. This unique case enabled the authors to examine their aims in the same patient with parent and daughter arteries under the same inlet flow conditions. Pulsatile flow in the aneurysm models was simulated using computational fluid dynamics and was validated with in vitro experiments using particle image velocimetry measurements. The authors’ detailed analysis of intrasaccular hemodynamics linked the growing regions of aneurysms to flow instabilities and complex vortex structures. Extremely low velocities were observed at or around the center of the unstable vortex structure, which matched well with the growing regions of the studied cerebral aneurysm. Furthermore, the authors observed that the aneurysm wall regions with a growth greater than 0.5 mm coincided with wall regions of lower (< 0.5 Pa) time-averaged wall shear stress (TAWSS), lower instantaneous (< 0.5 Pa) wall shear stress (WSS), and high (> 0.1) oscillatory shear index (OSI). To determine which set of parameters can best identify growing and nongrowing aneurysms, the authors performed statistical analysis for consecutive stages of the growing CA. The results demonstrated that the combination of TAWSS and the distance from the center of the vortical structure has the highest sensitivity and positive predictive value, and relatively high specificity and negative predictive value. These findings suggest that an unstable, recirculating flow structure within the aneurysm sac created in the region adjacent to the aneurysm wall with low TAWSS may be introduced as an accurate criterion to explain the hemodynamic conditions predisposing the aneurysm to growth. The authors’ findings are based on one patient’s data set, but the study lays out the justification for future large-scale verification. The authors’ findings can assist clinicians in differentiating stable and growing aneurysms during preinterventional planning.

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David A. Steinman and Vitor M. Pereira

Computational modeling of cerebral aneurysms, derived from clinical 3D angiography, has become widespread over the past 15 years. While such “image-based” or “patient-specific” models have shown promise for the assessment of rupture risk, much debate remains about their reliability in light of necessary modeling assumptions and incomplete or uncertain model input parameters derived from the clinic. The aims of this review were to walk through the various steps of this so-called patient-specific modeling pipeline and to highlight evidence supporting those steps that we can or cannot rely on. The relative importance of the different sources of error and variability on hemodynamic predictions is summarized, with recommendations to standardize for those that can be avoided and to pay closer attention those to that cannot.

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John W. Thompson, Omar Elwardany, David J. McCarthy, Dallas L. Sheinberg, Carlos M. Alvarez, Ahmed Nada, Brian M. Snelling, Stephanie H. Chen, Samir Sur and Robert M. Starke

Cerebral aneurysm rupture is a devastating event resulting in subarachnoid hemorrhage and is associated with significant morbidity and death. Up to 50% of individuals do not survive aneurysm rupture, with the majority of survivors suffering some degree of neurological deficit. Therefore, prior to aneurysm rupture, a large number of diagnosed patients are treated either microsurgically via clipping or endovascularly to prevent aneurysm filling. With the advancement of endovascular surgical techniques and devices, endovascular treatment of cerebral aneurysms is becoming the first-line therapy at many hospitals. Despite this fact, a large number of endovascularly treated patients will have aneurysm recanalization and progression and will require retreatment. The lack of approved pharmacological interventions for cerebral aneurysms and the need for retreatment have led to a growing interest in understanding the molecular, cellular, and physiological determinants of cerebral aneurysm pathogenesis, maturation, and rupture. To this end, the use of animal cerebral aneurysm models has contributed significantly to our current understanding of cerebral aneurysm biology and to the development of and training in endovascular devices. This review summarizes the small and large animal models of cerebral aneurysm that are being used to explore the pathophysiology of cerebral aneurysms, as well as the development of novel endovascular devices for aneurysm treatment.

Free access

Bart M. W. Cornelissen, Eva L. Leemans, Bram F. Coolen, Eva S. Peper, René van den Berg, Henk A. Marquering, Cornelis H. Slump and Charles B. L. M. Majoie

OBJECTIVE

MR vessel wall imaging (VWI) is increasingly performed in clinical settings to support treatment decision-making regarding intracranial aneurysms. Aneurysm wall enhancement after contrast agent injection is expected to be related to aneurysm instability and rupture status. However, the authors hypothesize that slow-flow artifacts mimic aneurysm wall enhancement. Therefore, in this phantom study they assess the effect of slow flow on wall-like enhancement by using different MR VWI techniques.

METHODS

The authors developed an MR-compatible aneurysm phantom model, which was connected to a pump to enable pulsatile inflow conditions. For VWI, 3D turbo spin echo sequences—both with and without motion-sensitized driven equilibrium (MSDE) and delay alternating with nutation for tailored excitation (DANTE) preparation pulses—were performed using a 3-T MR scanner. VWI was acquired both before and after Gd contrast agent administration by using two different pulsatile inflow conditions (2.5 ml/sec peak flow at 77 and 48 beats per minute). The intraluminal signal intensity along the aneurysm wall was analyzed to assess the performance of slow-flow suppression.

RESULTS

The authors observed wall-like enhancement after contrast agent injection, especially in low pump rate settings. Preparation pulses, in particular the DANTE technique, improved the performance of slow-flow suppression.

CONCLUSIONS

Near-wall slow flow mimics wall enhancement in VWI protocols. Therefore, VWI should be carefully interpreted. Preparation pulses improve slow-flow suppression, and therefore the authors encourage further development and clinical implementation of these techniques.

Free access

Peyton L. Nisson, Robert T. Wicks, Xiaochun Zhao, Whitney S. James, David Xu and Peter Nakaji

Cavernous malformations of the brain are low-flow vascular lesions that have a propensity to hemorrhage. Extensive surgical approaches are often required for operative cure of deep-seated lesions. A 23-year-old female presented with a cavernous malformation of the left posterior insula with surrounding hematoma measuring up to 3 cm. A minimally invasive (mini-)pterional craniotomy with a transsylvian approach was selected. Endoscopic assistance was utilized to confirm complete resection of the lesion. The minipterional craniotomy is a minimally invasive approach that provides optimal exposure for sylvian fissure dissection and resection of many temporal and insular lesions.

The video can be found here: https://youtu.be/9z6_EhU6lxs.