Mid-term safety and efficacy in small intracranial aneurysm coiling: results from TARGET® nano prospective independent core lab adjudicated multicenter registry.

Background: The primary objective is to evaluate the safety and effectiveness of Stryker second generation Target® Nano Coils in the treatment of ruptured and unruptured small (<7 mm) intracranial aneurysms. Methods: The TARGET Registry is a prospective, two-arm study with independent medical event monitoring and core-lab adjudication. This paper describes the second arm of the TARGET registry. Patients with de novo intracranial aneurysms were embolized with 2nd generation TARGET Nano coils in 12 US centers. The primary efficacy outcome was adequate aneurysm occlusion (RR occlusion grade I-II) on follow-up. Primary safety outcome was treatment-related morbidity and mortality. Secondary outcomes included aneurysm packing density immediately post-procedure, immediate adequate occlusion, aneurysm re-access rate, retreatment rate and clinical outcomes using modified ranking scale. A secondary analysis investigated the influence of using Nano-predominant coils (≥2/3 of total coil-length) vs. non-Nano-predominant coils (<2/3 of total length). Results: 150 patients with 155 aneurysms met the inclusion and exclusion criteria. (31%) patients with ruptured and (69%) with unruptured aneurysms were treated using TARGET coils. Median age was 58.8 (SD 12.7), 74.7% were females, and 80% were Caucasians. Mean follow-up was 5.23 (SD 2.27) months. Peri-procedural mortality was seen in 2.0% of patients. Good outcome at discharge (mRS 0-2) was seen in 81.3% of the cohort. The median packing density (SD) was 29.4% (14.9). Mid-term complete/near complete occlusion rate was seen in 96% of aneurysms and complete obliteration was seen in 75.2% of aneurysms. Patients treated predominantly with Nano coils had higher PD (32.6% vs. 26.1%, p < 0.001). There was no significant difference in clinical and angiographic outcomes. The mid-term mRS0-2 was achieved in 106/109 (97.2%) patients. All-cause mortality was 5/115 (4.3%). Conclusion: In the multicenter TARGET Registry, 75.8% of aneurysms achieved mid-term complete occlusion, and 96% achieved complete/near complete occlusion with excellent independent functional outcome.

Endogenous animal models of intracranial aneurysm development: a review.

The pathogenesis and natural history of intracranial aneurysm (IA) remains poorly understood. To this end, animal models with induced cerebral vessel lesions mimicking human aneurysms have provided the ability to greatly expand our understanding. In this review, we comprehensively searched the published literature to identify studies that endogenously induced IA formation in animals. Studies that constructed aneurysms (i.e., by surgically creating a sac) were excluded. From the eligible studies, we reported information including the animal species, method for aneurysm induction, aneurysm definitions, evaluation methods, aneurysm characteristics, formation rate, rupture rate, and time course. Between 1960 and 2019, 174 articles reported endogenous animal models of IA. The majority used flow modification, hypertension, and vessel wall weakening (i.e., elastase treatment) to induce IAs, primarily in rats and mice. Most studies utilized subjective or qualitative descriptions to define experimental aneurysms and histology to study them. In general, experimental IAs resembled the pathobiology of the human disease in terms of internal elastic lamina loss, medial layer degradation, and inflammatory cell infiltration. After the early 2000s, many endogenous animal models of IA began to incorporate state-of-the-art technology, such as gene expression profiling and 9.4-T magnetic resonance imaging (MRI) in vivo imaging, to quantitatively analyze the biological mechanisms of IA. Future studies aimed at longitudinally assessing IA pathobiology in models that incorporate aneurysm growth will likely have the largest impact on our understanding of the disease. We believe this will be aided by high-resolution, small animal, survival imaging, in situ live-cell imaging, and next-generation omics technology.

First off Label Endovascular Clinical Experience to Treat Diffuse Cerebral Venous Sinus Thrombosis Using the INARI FlowTriever System: Case Report.

Anticoagulation with heparin is the current mainstay treatment for Cerebral Venous Sinus Thrombosis (CVST). Endovascular treatment is increasingly being used to treat patients with CVST who are non-responsive to anticoagulation. These more aggressive interventions include catheter-based local chemical thrombolysis, balloon angioplasty and mechanical thrombectomy with uncertain safety and efficacy. Here we describe the first reported clinical experience using the INARI FlowTriever system to treat a patient presented with focal weakness and found to have diffuse CVST.

COVID-19 Era Stroke Service: Virtually Normal.

OBJECTIVE: To characterize my experience in the inpatient stroke service in an amusing fashion. BACKGROUND: The COVID-19 pandemic broke out during my time as a stroke fellow. It was a unique experience. METHODS: A non-exhaustive review of my memories as a stroke fellow during the COVID-19 pandemic was performed. I sat down and wrote the article. Then, I illustrated the figure. RESULTS: All results are not statistically significant unless otherwise noted. CONCLUSIONS: Zoom conferences are a promising technology for stroke services. Further studies are needed to further elucidate their benefits and drawbacks.

Patterns of Mechanical Thrombectomy for Stroke Before and After the 2015 Pivotal Trials and US National Guideline Update.

BACKGROUND: Positive pivotal trials followed by guideline endorsement can be a major driver of change in US national medical practice patterns. We therefore analyzed national trends in the use and outcomes of mechanical thrombectomy for acute ischemic stroke due to large vessel occlusion before and after the 2015 publication of pivotal trials and the US guideline update. METHODS: We analyzed the National Inpatient Sample from 2012-2016. Ischemic stroke and mechanical thrombectomy patients were identified using ICD-9 and ICD-10. The primary efficacy outcome measure was discharge to home, which strongly correlates with mild degree of disability at discharge. Safety outcomes include in-hospital mortality and in-hospital medical complications. RESULTS: From 2012-2016, 2,394,550 discharges were recorded with a diagnosis of ischemic stroke, including 39,150 (1.6%) treated with mechanical thrombectomy. The number and proportion of stroke patients undergoing mechanical thrombectomy annually rose from 4,910/452,905 (1.1%) in 2012 to 11,860/509,215 (2.3%) in 2016. The largest annual increase occurred between 2014, when 6,460 stroke patients were treated with thrombectomy, and 2015, when 10,280 underwent thrombectomy. Comparing the pre (Q1 2012 - Q4 2014) and post (Q4 2015 - Q4 2016) RCT/Guideline epochs, in addition to increased thrombectomy rates, the proportion of thrombectomy patients who received IV-tPA decreased (46% to 24%, p<0.001). Rates of mild disability outcome increased from 16% to 20% (p<0.001), while mortality decreased from 15% to 13% (p=0.01). The odds of pulmonary embolism, urinary tract infection, and pneumonia decreased, while intracerebral hemorrhage, septicemia, deep venous thrombosis, shock, and cardiac arrest were unchanged. CONCLUSION: In the United States, thrombectomy treatment for acute ischemic stroke increased rapidly and substantially in frequency following publication of positive clinical trials and US guideline update in 2015, accompanied by improved functional outcomes and reduced peri-procedural mortality.

Emerging therapies in acute ischemic stroke.

Thrombolysis and mechanical thrombectomy have revolutionized the care of patients with acute ischemic stroke. The number of patients who can benefit from these treatments continues to increase as new studies demonstrate that not just time since stroke onset but also collateral circulation influences outcome. Technologies such as telestroke, mobile stroke units, and artificial intelligence are playing an increasing role in identifying and treating stroke. Stroke-systems-of-care models continue to streamline the delivery of definitive revascularization in the age of mechanical thrombectomy.

Increasing prevalence of vascular risk factors in patients with stroke: A call to action.

OBJECTIVE: To evaluate trends in prevalence of cardiovascular risk factors (hypertension, diabetes, dyslipidemia, smoking, and drug abuse) and cardiovascular diseases (carotid stenosis, chronic renal failure [CRF], and coronary artery disease [CAD]) in acute ischemic stroke (AIS) in the United States. METHODS: We used the 2004-2014 National Inpatient Sample to compute weighted prevalence of each risk factor in hospitalized patients with AIS and used joinpoint regression to evaluate change in prevalence over time. RESULTS: Across the 2004-2014 period, 92.5% of patients with AIS had ≥1 risk factor. Overall age- and sex-adjusted prevalence of hypertension, diabetes, dyslipidemia, smoking, and drug abuse were 79%, 34%, 47%, 15%, and 2%, respectively, while those of carotid stenosis, CRF, and CAD were 13%, 12%, and 27%, respectively. Risk factor prevalence varied by age (hypertension: 44% in 18-39 years vs 82% in 60-79 years), race (diabetes: Hispanic 49% vs white 30%), and sex (drug abuse: men 3% vs women 1.4%). Using joinpoint regression, prevalence of hypertension increased annually by 1.4%, diabetes by 2%, dyslipidemia by 7%, smoking by 5%, and drug abuse by 7%. Prevalence of CRF, carotid stenosis, and CAD increased annually by 13%, 6%, and 1%, respectively. Proportion of patients with multiple risk factors also increased over time. CONCLUSIONS: Despite numerous guidelines and prevention initiatives, prevalence of hypertension, diabetes, dyslipidemia, smoking, and drug abuse in AIS increased across the 2004-2014 period. Proportion of patients with carotid stenosis, CRF, and multiple risk factors also increased. Enhanced risk factor modification strategies and implementation of evidence-based recommendations are needed for optimal stroke prevention.

Assessment of Vascular Geometry for Bilateral Carotid Artery Ligation to Induce Early Basilar Terminus Aneurysmal Remodeling in Rats.

Bilateral common carotid artery (CCA) ligation in rabbits is a model for basilar terminus (BT) aneurysm formation. We asked if this model could be replicated in rats. Fourteen female Sprague Dawley rats underwent bilateral CCA ligation (n=8) or sham surgery (n=6). After 7 days, 5 ligated and 3 sham rats were euthanized for histological evaluation of BT aneurysm formation, while the remaining rats were imaged with magnetic resonance angiography, euthanized, and subjected to corrosion casting of the Circle of Willis (CoW). 3D micro computed tomography images of CoW casts were used for flow simulations at the rat BT, and electron micrographs of the casts were analyzed for aneurysmal and morphological changes. Results from these analyses were compared to rabbit model data (n=10 ligated and n=6 sham). Bilateral CCA ligation did not produce aneurysmal damage at the rat BT. While the surgical manipulation increased rat basilar artery flow, fluid dynamics simulations showed that the initial hemodynamic stress at the rat BT was significantly less than in rabbits. Rats also exhibited fewer morphological and pathological changes (minor changes only occurred in the posterior CoW) than rabbits, which had drastic changes throughout the CoW. A comparison of CoW anatomies demonstrated a greater number of branching arteries at the BT, larger CoW arteries in relation to basilar artery, and a steeper BT bifurcation angle in the rat. These differences could account for the lower hemodynamic stress at the BT and in the cerebrovasculature of the rat. In conclusion, bilateral CCA ligation in rats does not recapitulate the rabbit model of early flow-induced BT aneurysm. We suspect that the different CoW morphology of the rat lessens hemodynamic insults, thereby diminishing flow-induced aneurysmal remodeling.

Endothelial nitric oxide synthase and superoxide mediate hemodynamic initiation of intracranial aneurysms.

BACKGROUND: Hemodynamic insults at arterial bifurcations are believed to play a critical role in initiating intracranial aneurysms. Recent studies in a rabbit model indicate that aneurysmal damage initiates under specific wall shear stress conditions when smooth muscle cells (SMCs) become pro-inflammatory and produce matrix metalloproteinases (MMPs). The mechanisms leading to SMC activation and MMP production during hemodynamic aneurysm initiation are unknown. The goal is to determine if nitric oxide and/or superoxide induce SMC changes, MMP production and aneurysmal remodeling following hemodynamic insult. METHODS: Bilateral common carotid artery ligation was performed on rabbits (n = 19, plus 5 sham operations) to induce aneurysmal damage at the basilar terminus. Ligated animals were treated with the nitric oxide synthase (NOS) inhibitor LNAME (n = 7) or the superoxide scavenger TEMPOL (n = 5) and compared to untreated animals (n = 7). Aneurysm development was assessed histologically 5 days after ligation. Changes in NOS isoforms, peroxynitrite, reactive oxygen species (ROS), MMP-2, MMP-9, and smooth muscle α-actin were analyzed by immunohistochemistry. RESULTS: LNAME attenuated ligation-induced IEL loss, media thinning and bulge formation. In untreated animals, immunofluorescence showed increased endothelial NOS (eNOS) after ligation, but no change in inducible or neuronal NOS. Furthermore, during aneurysm initiation ROS increased in the media, but not the intima, and there was no change in peroxynitrite. In LNAME-treated animals, ROS production did not change. Together, this suggests that eNOS is important for aneurysm initiation but not by producing superoxide. TEMPOL treatment reduced aneurysm development, indicating that the increased medial superoxide is also necessary for aneurysm initiation. LNAME and TEMPOL treatment in ligated animals restored α-actin and decreased MMPs, suggesting that eNOS and superoxide both lead to SMC de-differentiation and MMP production. CONCLUSION: Aneurysm-inducing hemodynamics lead to increased eNOS and superoxide, which both affect SMC phenotype, increasing MMP production and aneurysmal damage.

Progressive aneurysm development following hemodynamic insult.

OBJECT: Hemodynamic insult has been speculated to be a key factor in intracranial aneurysm formation; however, it is unclear whether a sustained insult is necessary. The authors examined whether aneurysmal degradation would continue despite the normalization of wall shear stress (WSS) by adaptive outward vascular remodeling. METHODS: Twenty-five rabbits underwent either sham operation (5 animals) or bilateral common carotid artery ligation (20 animals) to augment basilar artery (BA) flow. Basilar termini (BTs) were harvested at 5 days and 3, 12, and 27 weeks postoperation. Histological changes at the BTs were quantified using an aneurysm development score (ADS) wherein the luminal length of the vessel wall exhibiting internal elastic lamina (IEL) loss, media thinning (> 30% media loss), and bulging was multiplied by the percentage of media thinning divided by the BA diameter. This score and its component variables were evaluated over the specified time points and compared with the WSS time course obtained from multiple angiography and BA flow velocity measurements. RESULTS: Serial examination of histological sections from the ligation group (17 rabbits survived the procedure) demonstrated localized, progressive, degenerative, and aneurysmal changes at the BTs. Prominent IEL loss was observed in BT specimens from all ligated animals. Media thinning and luminal bulging significantly progressed over the 27-week follow-up. The composite ADS significantly increased over the study period, indicating progressive aneurysm development, although the WSS returned to preligation baseline values within 5 weeks of ligation. CONCLUSIONS: Hemodynamic insult can elicit a pathological vascular response leading to a self-sustaining aneurysmal remodeling that does not require persistence of the original inciting factor to continue its pathological progression.