Early Brain Injury After Subarachnoid Hemorrhage: Incidence and Mechanisms.

Aneurysmal subarachnoid hemorrhage is a devastating condition causing significant morbidity and mortality. While outcomes from subarachnoid hemorrhage have improved in recent years, there continues to be significant interest in identifying therapeutic targets for this disease. In particular, there has been a shift in emphasis toward secondary brain injury that develops in the first 72 hours after subarachnoid hemorrhage. This time period of interest is referred to as the early brain injury period and comprises processes including microcirculatory dysfunction, blood-brain-barrier breakdown, neuroinflammation, cerebral edema, oxidative cascades, and neuronal death. Advances in our understanding of the mechanisms defining the early brain injury period have been accompanied by improved imaging and nonimaging biomarkers for identifying early brain injury, leading to the recognition of an elevated clinical incidence of early brain injury compared with prior estimates. With the frequency, impact, and mechanisms of early brain injury better defined, there is a need to review the literature in this area to guide preclinical and clinical study.

Pediatric Thrombectomy: Design and Workflow Lessons From Two Experienced Centers.

Endovascular thrombectomy has played a major role in advancing adult stroke care and may serve a similar role in pediatric stroke care. However, there is a need to develop better evidence and infrastructure for pediatric stroke care. In this work, we review 2 experienced pediatric endovascular thrombectomy programs and examine key design features in both care environments, including a formalized protocol and workflow, integration with an adult endovascular thrombectomy workflow, simplification and automation of workflow steps, pediatric adaptations of stroke imaging, advocacy of pediatric stroke care, and collaboration between providers, among others. These essential features transcend any single hospital environment and may provide an important foundation for other pediatric centers that aim to enhance the care of children with stroke.

Neuropilin-2 regulates airway inflammatory responses to inhaled lipopolysaccharide.

Neuropilins are multifunctional receptors that play important roles in immune regulation. Neuropilin-2 (NRP2) is expressed in the lungs, but whether it regulates airway immune responses is unknown. Here, we report that Nrp2 is weakly expressed by alveolar macrophages (AMs) in the steady state but is dramatically upregulated following in vivo lipopolysaccharide (LPS) inhalation. Ex vivo treatment of human AMs with LPS also increased NRP2 mRNA expression and cell-surface display of NRP2 protein. LPS-induced Nrp2 expression in AMs was dependent upon the myeloid differentiation primary response 88 signaling pathway and the transcription factor NF-κB. In addition to upregulating display of NRP2 on the cell membrane, inhaled LPS also triggered AMs to release soluble NRP2 into the airways. Finally, myeloid-specific ablation of NRP2 resulted in increased expression of the chemokine (C-C motif) ligand 2 ( Ccl2) in the lungs and prolonged leukocyte infiltration in the airways following LPS inhalation. These findings suggest that NRP2 expression by AMs regulates LPS-induced inflammatory cell recruitment to the airways and reveal a novel role for NRP2 during innate immune responses in the lungs.

Role of microglia after subarachnoid hemorrhage.

Subarachnoid hemorrhage is a devastating sequela of aneurysm rupture. Because it disproportionately affects younger patients, the population impact of hemorrhagic stroke from subarachnoid hemorrhage is substantial. Secondary brain injury is a significant contributor to morbidity after subarachnoid hemorrhage. Initial hemorrhage causes intracranial pressure elevations, disrupted cerebral perfusion pressure, global ischemia, and systemic dysfunction. These initial events are followed by two characterized timespans of secondary brain injury: the early brain injury period and the delayed cerebral ischemia period. The identification of varying microglial phenotypes across phases of secondary brain injury paired with the functions of microglia during each phase provides a basis for microglia serving a critical role in both promoting and attenuating subarachnoid hemorrhage-induced morbidity. The duality of microglial effects on outcomes following SAH is highlighted by the pleiotropic features of these cells. Here, we provide an overview of the key role of microglia in subarachnoid hemorrhage-induced secondary brain injury as both cytotoxic and restorative effectors. We first describe the ontogeny of microglial populations that respond to subarachnoid hemorrhage. We then correlate the phenotypic development of secondary brain injury after subarachnoid hemorrhage to microglial functions, synthesizing experimental data in this area.

Peripheral macrophages in the development and progression of structural cerebrovascular pathologies.

The human cerebrovascular system is responsible for maintaining neural function through oxygenation, nutrient supply, filtration of toxins, and additional specialized tasks. While the cerebrovascular system has resilience imparted by elaborate redundant collateral circulation from supportive tertiary structures, it is not infallible, and is susceptible to developing structural vascular abnormalities. The causes of this class of structural cerebrovascular diseases can be broadly categorized as 1) intrinsic developmental diseases resulting from genetic or other underlying aberrations (arteriovenous malformations and cavernous malformations) or 2) extrinsic acquired diseases that cause compensatory mechanisms to drive vascular remodeling (aneurysms and arteriovenous fistulae). Cerebrovascular diseases of both types pose significant risks to patients, in some cases leading to death or disability. The drivers of such diseases are extensive, yet inflammation is intimately tied to all of their progressions. Central to this inflammatory hypothesis is the role of peripheral macrophages; targeting this critical cell type may lead to diagnostic and therapeutic advancement in this area. Here, we comprehensively review the role that peripheral macrophages play in cerebrovascular pathogenesis, provide a schema through which macrophage behavior can be understood in cerebrovascular pathologies, and describe emerging diagnostic and therapeutic avenues in this area.

Conditioning-based therapeutics for aneurysmal subarachnoid hemorrhage - A critical review.

Aneurysmal subarachnoid hemorrhage (SAH) carries significant mortality and morbidity, with nearly half of SAH survivors having major cognitive dysfunction that impairs their functional status, emotional health, and quality of life. Apart from the initial hemorrhage severity, secondary brain injury due to early brain injury and delayed cerebral ischemia plays a leading role in patient outcome after SAH. While many strategies to combat secondary brain injury have been developed in preclinical studies and tested in late phase clinical trials, only one (nimodipine) has proven efficacious for improving long-term functional outcome. The causes of these failures are likely multitude, but include use of therapies targeting only one element of what has proven to be multifactorial brain injury process. Conditioning is a therapeutic strategy that leverages endogenous protective mechanisms to exert powerful and remarkably pleiotropic protective effects against injury to all major cell types of the CNS. The aim of this article is to review the current body of evidence for the use of conditioning agents in SAH, summarize the underlying neuroprotective mechanisms, and identify gaps in the current literature to guide future investigation with the long-term goal of identifying a conditioning-based therapeutic that significantly improves functional and cognitive outcomes for SAH patients.

In-hospital imaging utilization after elective endovascular brain aneurysm treatment: a surrogate metric for the value of hospitalization.

OBJECTIVE: Despite the adoption of same-day outpatient surgical procedures in some specialties, it remains common practice to admit patients for monitoring after elective endovascular treatment of brain aneurysms to monitor for complications. The necessity of such monitoring has not been fully characterized. Here, the authors reviewed the utilization of imaging during posttreatment hospitalization, a surrogate measure for workup of suspected complications requiring hospital resources, to infer the value of inpatient monitoring after endovascular aneurysm treatment. METHODS: Clinical and angiographic data from eligible patients were retrospectively assessed for demographic characteristics, imaging indications, timing of imaging, and imaging findings. Patients were included if they underwent elective endovascular brain aneurysm treatment, and patients were excluded if significant intraprocedural complications occurred. The recorded imaging modalities included CT, MRI, catheter-based imaging, and ultrasound; plain radiographs were excluded. Multivariable logistic regression analysis was performed to identify predictors of the need for posttreatment imaging. RESULTS: In total, 1229 elective endovascular procedures for brain aneurysm treatment were included. Patients underwent imaging before discharge in 13.4% (165/1229) of cases, with significant findings in 5.0% (61/1229) of cases. The median (interquartile range) time to first posttreatment imaging was 13.2 (4.2-22.8) hours. The need for imaging during posttreatment hospitalization was positively associated with larger aneurysm size (p < 0.05) and negatively associated with underlying cardiovascular disease (p < 0.05). CONCLUSIONS: More than 1 in 8 patients who underwent elective endovascular brain aneurysm treatment required imaging during posttreatment hospitalization, most within the first 24 hours, and 1 in 20 had significant findings. These results suggest the importance of short-term hospitalization after elective endovascular aneurysm treatment.

Etiologies of Brain Arteriovenous Malformation Recurrence: A Focus on Pediatric Disease.

Pediatric brain arteriovenous malformations are a major cause of morbidity and mortality, with the harmful effects of this disease compounded by the additional disability-years experienced by children with ruptured or other symptomatic arteriovenous malformations. In addition to the risks shared with their adult counterparts, pediatric patients frequently experience recurrence following radiographic cure, which presents an additional source of morbidity and mortality. Therefore, there is a need to synthesize potential mechanisms contributing to the elevated recurrence risk in the pediatric population and discuss how these translate to practical considerations for managing these patients.

Idiopathic Intracranial Hypertension and Vascular Anomalies in Chiari I Malformation.

Mounting evidence has suggested a relationship between Chiari I malformation and idiopathic intracranial hypertension, with some studies implicating anomalies of the cerebral venous system in the development of these conditions. However, precise mechanisms explaining these associations are not well described. There is a clear need to clarify the interplay between these conditions to guide further study in this area. In tandem with these efforts, it is necessary to review proper diagnosis and management to improve outcomes in patients suffering from these diseases.

Endovascular treatment of dural arteriovenous fistulas involving the vein of Galen: a single-center cohort and meta-analysis.

BACKGROUND: Dural arteriovenous fistulas (dAVFs) draining into the vein of Galen (VoG) are complex lesions that often necessitate treatment to minimize the risk of rupture and relieve symptoms. These lesions can be treated with open surgical resection, radiosurgery, or endovascular embolization. Unfortunately, endovascular treatment of dAVFs involving the VoG has not been robustly assessed across large patient cohorts. To meet this need, we performed a retrospective review of dAVFs involving the VoG at our center, and included these in a meta-analysis to identify the safety and efficacy of endovascular embolization, as well as describing current treatment trends for this disease. METHODS: Consecutive patients with dAVFs involving the VoG treated at a single center were identified from a prospective database and retrospectively reviewed. A literature search was conducted with defined search criteria, and eligible studies were included alongside our cohort in a meta-analysis. Rates of complete dAVF treatment and clinical complications were pooled across studies with a random effects model and reported with a 95% CI. RESULTS: Five dAVFs involving the VoG were treated endovascularly at our center during the study period. In this series, 80% of treatments led to complete occlusion of the fistula while no patients had clinical complications. Onyx was used for all treatments. In our meta-analysis, the overall rate of complete occlusion was 72.0% (95% CI 59.8% to 84.1%) and the overall rate of clinical complications was 10.0% (95% CI 4.7% to 15.3%). CONCLUSIONS: Endovascular approaches for dAVFs involving the VoG are technically feasible, but carry a risk of clinical complications. Future work should identify optimal endovascular embolic agents.

Retreatment of previously flow diverted intracranial aneurysms with the pipeline embolization device.

BACKGROUND AND PURPOSE: Flow diversion of intracranial aneurysms with the Pipeline Embolization Device (PED) is frequently performed, but the outcomes of retreatment for aneurysms that failed to occlude after prior treatment with PED have not been well studied. Here, we report the safety and efficacy of PED retreatment after initial failure to occlude. MATERIALS AND METHODS: Clinical and angiographic data from eligible patients were retrospectively assessed for demographics, aneurysm occlusion status, and clinical outcomes. Patients were included in this study if they underwent PED retreatment to treat an aneurysm that had previously been treated with PED. RESULTS: Retreatment of previously flow-diverted aneurysms with PED was performed in 42 cases. At final angiographic follow-up, angiographic improvement was observed after 45% (19/42) of retreatments and complete aneurysm occlusion was observed following 26% (11/42). Significant clinical complications occurred in 10% (4/42) of PED retreatments. CONCLUSIONS: Retreatment of intracranial aneurysms with PED following initial failure to achieve aneurysm occlusion has a low rate of subsequent complete aneurysm occlusion.

Need for Y-stenting in stent-assisted coiling of wide-neck bifurcation aneurysms.

BACKGROUND AND PURPOSE: Stent-assisted coiling of wide neck bifurcation aneurysms in the anterior communicating segment and basilar tip region can be performed with varying stent configurations, including single stenting or Y-stenting. Y-stenting requires two stents and thus incurs greater cost and procedural complexity than single-stent constructs. The influence of first stent type on the need for Y-stenting remains unknown. MATERIALS AND METHODS: Clinical and angiographic data were retrospectively obtained for patients that underwent stent-assisted coiling for basilar tip or anterior communicating aneurysms at a high-volume center. Patients were included in this study if stent-assisted coiling was performed using Neuroform Atlas or LVIS Jr stents. A multivariate binary logistic regression was performed to measure the influence of first stent type on the need for Y-stenting. RESULTS: Stent-assisted coiling was used to treat 82 aneurysms in 81 patients during the study period, and Y-stenting was performed in 18.3% (15/82) of cases. In multivariate logistic regression analysis, use of LVIS Jr. as the first stent did not significantly influence the need for subsequent Y-stenting after controlling for aneurysm morphology (OR 0.65, 95% CI 0.18-2.43). CONCLUSION: Controlling for aneurysm morphology and location, the use of Y-stenting for stent-assisted coiling was not independently influenced by the choice of LVIS Jr or Neuroform Atlas as the first stent. A larger cohort may reveal differences between these two stents, particularly for aneurysms with large neck sizes.

A review of technological innovations leading to modern endovascular brain aneurysm treatment.

Tools and techniques utilized in endovascular brain aneurysm treatment have undergone rapid evolution in recent decades. These technique and device-level innovations have allowed for treatment of highly complex intracranial aneurysms and improved patient outcomes. We review the major innovations within neurointervention that have led to the current state of brain aneurysm treatment.

Comparative cost analysis of endovascular and open approaches for elective treatment of middle cerebral artery aneurysms.

BACKGROUND: Intracranial aneurysms of the middle cerebral artery can be treated using several open surgical and endovascular approaches. Given the growing evidence of clinical equipoise between these various treatment strategies, there is a need to assess the costs associated with each. METHODS: Cost of aneurysm treatment was divided into two categories for comparison. "Initial cost" comprised the total in-hospital expenses for initial aneurysm treatment and "total cost" comprised initial aneurysm treatment and all expenses relating to readmission due to treatment-related complications, prescribed catheter angiograms for monitoring of treatment stability, and any retreatments needed for a given aneurysm. The open surgical group was subdivided into a pterional approach group and a lateral supraorbital (LSO) approach group for. RESULTS: Median initial cost was $37,152 (IQR $31,318-$44,947) for aneurysms treated with the pterional approach, $29,452 (IQR $27,779-$32,826) for aneurysms treated with the LSO approach, and $19,587 (IQR $14,125-$30,521) for aneurysms treated with endovascular approaches. The median total cost was $39,737 (IQR $33,891-$62,259) for aneurysms treated with the pterional approach, $31,785 (IQR $29,513-$41,099) for aneurysms treated with the LSO approach, and $24,578 (IQR $18,977-$34,547) for aneurysms treated with endovascular approaches. Analysis of variance test demonstrated variance across groups for both initial and total cost (p = 0.004, p = 0.008, respectively). In our subsequent analysis, initial cost and total cost were higher in the pterional group than the endovascular group (p = 0.003 and p = 0.006, respectively). CONCLUSIONS: Endovascular treatment of elective aneurysms has a significantly lower cost than open surgical treatment with the pterional approach, but not with the LSO approach. For aneurysms not amenable to endovascular treatment, a minimally invasive LSO approach carries a lower cost burden than a pterional approach.

Neurointerventional management of cerebrovascular trauma.

Traumatic cerebrovascular injuries following blunt or penetrating trauma are common and carry a high risk of permanent disability or death. Proper screening, diagnosis, and treatment of these lesions is essential to improve patient outcomes. Advances in imaging continue to improve the accuracy of non-invasive diagnosis of these injuries while new clinical data provide better evidence for optimal management, whether medical or invasive. Here, we review screening, diagnosis, and treatment of traumatic cerebrovascular injuries.

Safety of pediatric cerebral angiography.

OBJECTIVE: Catheter-based cerebral angiography is commonly used for neurovascular diagnosis in children. In this work, the authors aimed to quantify the complication rate of cerebral angiography in children, characterize these complications, and identify risk factors for complications. METHODS: Relevant clinical data were retrospectively obtained for 587 consecutive cerebral angiography procedures performed in 390 children from March 2002 to March 2020. Complications were categorized as neurological or nonneurological, and severity was graded using a standard schema. Incidences of complications were reported as point estimates. Associations between risk factors and complications were characterized in univariate analysis using the two-tailed Fisher exact test and in multivariate analysis using multiple logistic regression with bidirectional elimination based on the Akaike information criterion. In both univariate and multivariate analyses, statistical significance was corrected for multiple comparisons using the Benjamini-Hochberg method. RESULTS: Complications occurred in 6.5% of procedures, including neurological complications in 1.9% and nonneurological complications in 4.8%. Permanent deficits occurred in only 0.2% of cases. Overall, 0.5% of procedures resulted in major complications, while 6.0% resulted in minor complications. Female sex and a history of hypertension or ischemic stroke were associated with an increased risk of complications, while femoral artery access was associated with a decreased risk of complications. CONCLUSIONS: Pediatric cerebral angiography was shown to have a low rate of major or permanent complications. Children who were female and those with a history of hypertension or ischemic stroke were shown to be at higher risk of complications, while the use of femoral access carried a lower risk of complications.

The value of long-term angiographic follow-up following Pipeline embolization of intracranial aneurysms.

BACKGROUND: Flow diversion of intracranial aneurysms with the Pipeline Embolization Device (PED) is commonly performed, but the value of long-term angiographic follow-up has not been rigorously evaluated. Here we examine the prevalence of actionable findings of aneurysm recurrence and development of in-stent stenosis in a cohort of patients that underwent long-term angiographic follow-up at multiple time points. METHODS: Angiographic data from eligible patients were retrospectively assessed for aneurysm occlusion, in-stent stenosis, and aneurysm regrowth or recurrence. Patients were included in this study if they underwent angiographic imaging at 6 months post-treatment and at least one later time point. RESULTS: 100% (132/132) of aneurysms occluded at 6 months remained occluded at final follow-up. 85.7% (6/7), 56.3% (27/48), and 25% (6/24) of aneurysms with entry remnant, subtotal filling, and total filling, respectively, at 6 months were completely occluded at final follow-up. 98.7% (147/149) of PED constructs that demonstrated no stenosis at 6 months demonstrated no stenosis at final angiography, while 44.4% (8/18) of PED constructs demonstrating in-stent stenosis at 6 months had resolution of stenosis on final angiography. CONCLUSIONS: Among patients who undergo treatment of intracranial aneurysms with PED, the value of long-term angiography in patients demonstrating complete aneurysm occlusion and no in-stent stenosis on 6 month post-treatment angiography is low.

Time Line of Occlusion for Intracranial Aneurysms Treated with the Pipeline Embolization Device.

BACKGROUND: Rates of aneurysm occlusion following treatment with flow-diverting stents have been quantified at predefined time points in clinical trials, but data characterizing the continuous temporal progression of aneurysm occlusion are lacking. This study used real-world variability in timing of angiographic follow-up to characterize the time line of aneurysm occlusion following treatment with the Pipeline embolization device (PED). METHODS: All aneurysms treated with a PED at our institution between 2011 and 2020 were screened. Nonsaccular or ruptured aneurysms were excluded. Aneurysm occlusion status and time since treatment were recorded for each follow-up angiogram. Aneurysm occlusion was characterized using Kaplan-Meier and Cox proportional hazards analysis after censoring at last follow-up or subsequent treatment. RESULTS: There were 290 aneurysms in 222 patients analyzed. The median time of observed aneurysm occlusion was 7.5 months, and overall rate of aneurysm occlusion was 77.9%. Larger aneurysms demonstrated a longer median time to occlusion and lower rate of aneurysm occlusion (P = 0.029). There were no observed differences in the time line of occlusion for aneurysms treated with a single PED or multiple PEDs (P = 0.889) or without or with adjunctive coiling (P = 0.771). CONCLUSIONS: Aneurysms treated with a PED had a median time to observed occlusion of 7.5 months. Occlusion of larger aneurysms occurred more slowly than occlusion of smaller aneurysms following flow diversion. The number of PEDs deployed or the use of adjunctive coiling did not affect the time line or likelihood of aneurysm occlusion. These findings may guide optimal timing of follow-up after treatment with a PED.