Low-profile mechanical thrombectomy devices for large vessel occlusion in pediatric ischemic stroke.

BACKGROUND: Mechanical thrombectomy (MT) is a well-established treatment modality for large vessel occlusion (LVO) in adults, but there are limited data in the pediatric population. The rarity of the condition makes prospective trial design difficult, and therefore evaluation of MT devices and outcomes is sparse. In pediatric LVO cases, some newer devices may be appropriate for use in revascularization procedures. Furthermore, illustrative specific device-access combinations have rarely been presented in young patients under the age of 5 years. METHODS: This was a single institution experience in intracranial MT procedures for pediatric acute ischemic stroke (AIS). A given procedure was included if there was an attempt at MT between 2015 and 2023. RESULTS: Sixteen endovascular procedures were performed in 15 patients with AIS, with a mean age of 7.4 years; eight patients were <5 years of age. MT was attempted in 15/16 (93.7%) procedures, including 11 (73.3%) in the anterior circulation and four (26.7%) in the posterior circulation; one case recanalized after medical treatment. The most common MT techniques were combined aspiration with a stentriever (n=10, 66.7%) and aspiration alone (n=3, 20%). Traditional stentrievers (4-6 mm) were used in seven cases and low-profile stentrievers in four cases. Improved reperfusion was achieved in all low-profile stentriever cases. Reperfusion of modified Thrombolysis in Cerebral Infaction ≥2b was obtained in 73.3% of cases, including 72.7% of those in which a stentriever was used. CONCLUSIONS: Low-profile thrombectomy devices may achieve similar revascularization results to other approaches in challenging clinical scenarios observed in younger children.

A Review of the Current State and Future Directions for Management of Scalp and Facial Vascular Malformations.

Vascular malformations are structural abnormalities that are thought to result from errors in vasculogenesis and angiogenesis during embryogenesis. Vascular malformations of the scalp present unique management challenges due to aesthetic and functional implications. This review examines the pathophysiology, clinical presentation, and management techniques for six common types of vascular malformations of the face and scalp : infantile hemangioma, capillary malformations, venous malformations, lymphatic malformations, arteriovenous malformations, and arteriovenous fistulas. These lesions range from common to rare, and have very different natural histories and management paradigms. There has been increasing understanding of the molecular pathways that are altered in association with these vascular lesions and these molecular targets may represent novel strategies of treating lesions that have historically been approached from a structural perspective only.

Comparing Vascular Morphology and Hemodynamics in Patients with Vein of Galen Malformations Using Intracranial 4D Flow MRI.

BACKGROUND AND PURPOSE: Vein of Galen malformation (VOGM) is the most common congenital cerebrovascular malformation, and many patients have high mortality rates and poor cognitive outcomes. Quantitative diagnostic tools are needed to improve clinical outcomes, and the purpose of this study was to characterize intracranial blood flow in VOGM using quantitative 4D flow MRI. MATERIALS AND METHODS: A prospective study of children with VOGM was conducted by acquiring 4D flow MRI to quantify total blood inflow to the brain, flow in the pathologic falcine sinus, and flow in the superior sagittal sinus. Linear regression was used to test the relationships between these flows and age, clinical status, and the mediolateral diameter of the outflow tract of the lesion through the falcine or straight sinus diameter, which is a known morphologic prognostic metric. RESULTS: In all 11 subjects (mean age, 22 [SD,17 ] weeks), total blood flow to the brain always exceeded normal levels (mean, 1063 [SD, 403] mL/minute). Significant correlations were observed between falcine sinus flow and the mediolateral diameter of the straight or falcine sinus, the posterior cerebral artery/MCA flow ratio and age at scanning, and superior sagittal sinus flow proximal to malformation inflow and age at scanning. CONCLUSIONS: Using 4D flow MRI, we established the hemodynamic underpinnings of the mediolateral diameter of the straight or falcine sinus and investigated metrics representing parenchymal venous drainage that could be used to monitor the normalization of hemodynamics during embolization therapy.

Management of Pediatric Intracranial Arteriovenous Malformations.

Pediatric intracranial arteriovenous malformations (AVMs) are challenging lesions managed by pediatric neurosurgeons. The high risk of hemorrhage and neurologic injury is compounded by the unique anatomy of each malformation that requires individualizing treatment options. This article reviews the current status of pediatric AVM epidemiology, pathophysiology and clinical care, with a specific focus on the rationale and methodology of surgical resection.

Rupture risk and outcomes of giant aneurysms in pediatric patients: a multi-institutional case series and systematic review.

OBJECTIVE: Giant aneurysms in pediatric patients are vascular lesions that can cause significant neurological morbidity and mortality. Their rarity has precluded large cohort studies to inform their management. The objective of this study was to understand the clinical course and outcomes of giant aneurysms in pediatric patients. METHODS: The authors performed a multi-institutional cohort study of cases from Boston Children's Hospital and Barrow Neurological Institute, as well as a systematic review and pooled cohort analysis of previously reported cases using descriptive statistics and multivariate regression modeling. RESULTS: Fifteen patients were included in the multi-institutional cohort, and an additional 88 patients were included from 14 series, yielding 103 patients within the pooled cohort. Among the pooled cohort, the most common aneurysm locations were in the middle cerebral artery (36%), internal carotid artery (27%), vertebral artery (11%), and vertebrobasilar junction (8%). Within 69 cases containing radiographic data in the analysis, 38% of aneurysms were saccular. Twenty-eight cases presented with aneurysm rupture (28%), including 0% of cavernous carotid aneurysms, 26% of other anterior circulation aneurysms, and 44% of posterior circulation aneurysms (p = 0.003). In multivariate analysis, posterior circulation location (OR 2.66, 95% CI 1.03-6.86) and younger age (OR 0.90 per year, 95% CI 0.81-1.00) were associated with aneurysm rupture presentation. Most cases were treated (97%) rather than observed (3%). The mortality rate was 3% for unruptured aneurysms and 18% for ruptured aneurysms. A favorable neurological outcome occurred in 80% of unruptured aneurysm cases and 54% of ruptured cases. In multivariate analysis, unruptured aneurysm presentation (OR 3.74, 95% CI 1.24-11.29) and endovascular treatment modality (OR 5.05, 95% CI 1.56-16.29) were associated with a favorable outcome. CONCLUSIONS: Giant aneurysms are rare entities in pediatric patients that are unlikely to be discovered incidentally and usually merit treatment. Most patients survive with good neurological outcome, even in ruptured aneurysm cases. These data reveal that posterior circulation location and younger age are risk factors that correlate with an increased risk of aneurysm rupture.

Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations.

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and most severe of congenital brain arteriovenous malformations, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (2042.5-fold, p = 4.79 x 10-7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (17.5-fold, p = 1.22 x 10-5), which cooperates with p120 RasGAP to regulate vascular development. Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomic analysis defined developing endothelial cells as a likely spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis and impaired hierarchical development of arterial-capillary-venous networks, but only in the presence of a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have implications for patients and their families.

SUMOtherapeutics for Ischemic Stroke.

The small, ubiquitin-like modifier (SUMO) is a post-translational modifier with a profound influence on several key biological processes, including the mammalian stress response. Of particular interest are its neuroprotective effects, first recognized in the 13-lined ground squirrel (Ictidomys tridecemlineatus), in the context of hibernation torpor. Although the full scope of the SUMO pathway is yet to be elucidated, observations of its importance in managing neuronal responses to ischemia, maintaining ion gradients, and the preconditioning of neural stem cells make it a promising therapeutic target for acute cerebral ischemia. Recent advances in high-throughput screening have enabled the identification of small molecules that can upregulate SUMOylation, some of which have been validated in pertinent preclinical models of cerebral ischemia. Accordingly, the present review aims to summarize current knowledge and highlight the translational potential of the SUMOylation pathway in brain ischemia.

Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations.

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and severe congenital brain arteriovenous malformation, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP ( RASA1 ) harbored a genome-wide significant burden of loss-of-function de novo variants (p=4.79×10 -7 ). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 ( EPHB4 ) (p=1.22×10 -5 ), which cooperates with p120 RasGAP to limit Ras activation. Other probands had pathogenic variants in ACVRL1 , NOTCH1 , ITGB1 , and PTPN11 . ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomics defined developing endothelial cells as a key spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant exhibited constitutive endothelial Ras/ERK/MAPK activation and impaired hierarchical development of angiogenesis-regulated arterial-capillary-venous networks, but only when carrying a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have clinical implications.

Percutaneous transuterine fetal cerebral embolisation to treat vein of Galen malformations at risk of urgent neonatal decompensation: study protocol for a clinical trial of safety and feasibility.

INTRODUCTION: Although endovascular techniques have improved outcomes in vein of Galen malformations (VOGM), there is still a high rate of morbidity and mortality, particularly among cases with decompensation in the neonatal period. The dimension of the draining venous sinus on fetal imaging correlates with the risk of neonatal decompensation. In fetuses within this high-risk group who do not have end-organ injury, there is a theoretical therapeutic opportunity to reduce the arteriovenous shunt before the normal physiological changes of birth precipitate decompensation. This study investigates the safety and potential benefit of treating a VOGM in utero, which has not been previously studied. METHODS AND ANALYSIS: This study aims to enroll 20 subjects: pregnant women with a fetus harbouring a high-risk VOGM (defined on MRI by a narrowest medial-lateral width greater than 8 mm in the draining venous sinus). Unfortunately, the subset of fetuses with in utero end-organ injury is ineligible, because the late stage of pathology is not amenable to recovery from a cerebrovascular intervention, likely not even in utero. This study aims to alter the physiology before such developments accrue.At or after 23 weeks of gestation, a transuterine transposterior fontanelle needle puncture to the torcular allows ultrasound-guided deployment of coils to embolise the draining venous malformation.This study has 97.5% power to detect major safety events at 30% or greater, and 80% power to detect a reduction in the rate of neonatal intervention from 80% to 30%. In the staged study design, an interval evaluation after 11 patients invokes study termination if safety events occur above the allowed threshold. ETHICS AND DISSEMINATION: The institutional review boards at Mass General Brigham and Boston Children's Hospital (BCH) reviewed and approved this protocol. The BCH Department of Radiology and a patient family philanthropic donation fund this study. The trial results will be published in peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION NUMBER: NCT04434729.

Microsurgical Ligation of Residual Fistulous Arteriovenous Shunt From a Radicular Artery to a Thoracic Arteriovenous Malformation: 2-Dimensional Operative Video.

The literature has long attempted distinct classifications of arteriovenous fistulae and arteriovenous malformations of the spine.1-3 It is worth noting that lesions can become more complex during recurrence and may not adhere to traditional definitions. In these cases, recognizing the principles of pathology and pathophysiology can guide management and treatment. We present the case of a spinal arteriovenous malformation with recurrence after prior treatment that is managed in the setting of a second opinion with a multidisciplinary approach. This case demonstrates (1) an evolution of recurrent arteriovenous shunting pathology observed both in the endovascular suite, and under direct microscopic visualization and (2) considerations in multimodal treatment with endovascular devices during microsurgical dissection and extirpation. This manuscript was prepared with informed assent provided by the patient (a minor) and with informed consent by the parent of the patient, who is their legal representative and health-care proxy.

Noninfectious Fever in Aneurysmal Subarachnoid Hemorrhage: Association with Cerebral Vasospasm and Clinical Outcome.

OBJECTIVE: The purpose of this study was to evaluate the association between noninfectious fever onset and radiographic vasospasm, delayed ischemic neurologic deficit (DIND), delayed cerebral infarction (DCI), and clinical outcome in patients with aneurysmal subarachnoid hemorrhage. METHODS: We evaluated 44 patients for the association between noninfectious fever (greater than 101.5°F) and the development of radiographic vasospasm by digital subtraction angiography (DSA) and transcranial Doppler (TCD), DIND, DCI, and modified Rankin scale outcome score at 6 months to 2 years. Multivariate logistic regression analyses were performed to account for patient age, sex, admission Hunt and Hess grade, and Fisher grade. TCD was additionally used for temporal analysis. RESULTS: Noninfectious fever was significantly associated with radiographic vasospasm using both DSA (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.2-4.5; P = 0.02) and TCD (OR, 2.4; 95% CI, 1.2-5.6; P = 0.02), but it was not associated with DIND, DCI, or outcome. The maximum cross correlation between TCD velocity and temperature occurred for temperatures taken 1 day prior to TCD velocity measurement. A quadratic mixed-effects model demonstrated that TCD velocity was significantly associated with temperature from 1 day prior to TCD velocity measurement (ß = 13.5; 95% CI, 0.83-8.79, P = 0.01), posthemorrhage day (ß = 20.1; 95% CI, 2.14-7.52; P < 0.001), and (posthemorrhage day)2 (ß = -0.72; 95% CI, -0.26 to -0.11; P < 0.001). CONCLUSIONS: Noninfectious fever was associated with the development of radiographic vasospasm but not with DIND, DCI, or clinical outcome. Furthermore, there is a temporal association between the onset of noninfectious fever and radiographic vasospasm by 1 day. Fever independent of patient's infectious profile may be an early marker for the development of radiographic vasospasm.