Perioperative Management of Pediatric Patients with Moyamoya Arteriopathy.

Pediatric patients with moyamoya arteriopathy are at high risk for developing new onset transient or permanent neurologic deficits secondary to cerebral hypoperfusion, particularly in the perioperative period. It is therefore essential to carefully manage these patients in a multidisciplinary, coordinated effort to reduce the risk of new permanent neurologic deficits. However, little has been published on perioperative management of pediatric patients with moyamoya, particularly in the early postoperative period during intensive care unit admission. Our pediatric neurocritical care team sought to create a multidisciplinary periprocedural evidence- and consensus-based care pathway for high-risk pediatric patients with moyamoya arteriopathy undergoing anesthesia for any reason to decrease the incidence of periprocedural stroke or transient ischemic attack (TIA). We reviewed the literature to identify risk factors associated with perioperative stroke or TIA among patients with moyamoya and to gather data supporting specific perioperative management strategies. A multidisciplinary team from pediatric anesthesia, neurocritical care, nursing, child life, neurosurgery, interventional neuroradiology, neurology, and hematology created a care pathway for children with moyamoya undergoing anesthesia, classifying them as either high or standard risk, and applying an individualized perioperative management plan to high-risk patients. The incidence of neurologic sequelae before and after pathway implementation will be compared in future studies.

Cochlear Aqueduct Morphology in Superior Canal Dehiscence Syndrome.

The cochlear aqueduct (CA) connects the scala tympani to the subarachnoid space and is thought to assist in pressure regulation of perilymph in normal ears, however, its role and variation in inner ear pathology, such as in superior canal dehiscence syndrome (SCDS), is unknown. This retrospective radiographic investigation compared CA measurements and classification, as measured on flat-panel computerized tomography, among three groups of ears: controls, n = 64; anatomic superior canal dehiscence without symptoms (SCD), n = 28; and SCDS, n = 64. We found that in a multinomial logistic regression adjusted for age, sex, and BMI, an increase in CA length by 1 mm was associated with a lower odds for being in the SCDS group vs. control (Odds ratio 0.760 p = 0.005). Hierarchical clustering of continuous CA measures revealed a cluster with small CAs and a cluster with large CAs. Another multinomial logistic regression adjusted for the aforementioned clinical covariates showed an odds ratio of 2.97 for SCDS in the small CA cluster as compared to the large (p = 0.004). Further, no significant association was observed between SCDS symptomatology-vestibular and/or auditory symptoms-and CA structure in SCDS ears. The findings of this study lend support to the hypothesis that SCDS has a congenital etiology.

Childhood Brain Tumors: A Review of Strategies to Translate CNS Drug Delivery to Clinical Trials.

Brain and spinal tumors affect 1 in 1000 people by 25 years of age, and have diverse histological, biological, anatomical and dissemination characteristics. A mortality of 30-40% means the majority are cured, although two-thirds have life-long disability, linked to accumulated brain injury that is acquired prior to diagnosis, and after surgery or chemo-radiotherapy. Only four drugs have been licensed globally for brain tumors in 40 years and only one for children. Most new cancer drugs in clinical trials do not cross the blood-brain barrier (BBB). Techniques to enhance brain tumor drug delivery are explored in this review, and cover those that augment penetration of the BBB, and those that bypass the BBB. Developing appropriate delivery techniques could improve patient outcomes by ensuring efficacious drug exposure to tumors (including those that are drug-resistant), reducing systemic toxicities and targeting leptomeningeal metastases. Together, this drug delivery strategy seeks to enhance the efficacy of new drugs and enable re-evaluation of existing drugs that might have previously failed because of inadequate delivery. A literature review of repurposed drugs is reported, and a range of preclinical brain tumor models available for translational development are explored.

Definitive treatment of seizures due to hemimegalencephaly in neonates and young infants by transarterial embolization: technical considerations for 'endovascular embolic hemispherectomy'.

BACKGROUND: This case series describes the technical considerations and effectiveness of 'endovascular embolic hemispherectomy' for the treatment of medically intractable seizures in neonates and young infants with hemimegalencephaly (HME) and in whom surgical hemispherectomy is not a viable option. METHODS: This is a descriptive review of the endovascular technique used to treat consecutive pediatric patients with serial transarterial embolization for intractable seizures due to HME between 2018 and 2022. Clinical presentation, endovascular procedural details and complications, and efficacy were examined. RESULTS: Three infants (13-day-old, 13-week-old and 15-day-old) with HME and intractable seizures underwent a total of 10 transarterial embolizations. Anticipated intraprocedural events included vasospasm and focal subarachnoid hemorrhage in all three infants, effectively controlled endovascularly, and non-target embolization in one infant. No infants had symptomatic intracranial hemorrhage or femoral artery occlusion. EEG background quiescence and seizure cessation was achieved after the final stage of embolization in all patients. All infants were discharged home from the neonatal ICU (median length of stay 36 days, range 27-74 days) and remain seizure-free to date (4 years, 9 months, and 8 months). None have developed hydrocephalus, required surgical hemispherectomy or other neurosurgical interventions. CONCLUSION: Endovascular hemispherectomy can be safely used to provide definitive treatment of HME-related epilepsy in neonates and young infants when intraprocedural events are managed effectively. This less invasive novel approach should be considered a feasible early alternative to surgical hemispherectomy. Further studies are needed to enhance the safety profile and to assess long-term neurodevelopmental outcome and durability of freedom from seizures.

Hyperosmolar blood-brain barrier opening using intra-arterial injection of hyperosmotic mannitol in mice under real-time MRI guidance.

The blood-brain barrier (BBB) is the main obstacle to the effective delivery of therapeutic agents to the brain, compromising treatment efficacy for a variety of neurological disorders. Intra-arterial (IA) injection of hyperosmotic mannitol has been used to permeabilize the BBB and improve parenchymal entry of therapeutic agents following IA delivery in preclinical and clinical studies. However, the reproducibility of IA BBB manipulation is low and therapeutic outcomes are variable. We demonstrated that this variability could be highly reduced or eliminated when the procedure of osmotic BBB opening is performed under the guidance of interventional MRI. Studies have reported the utility and applicability of this technique in several species. Here we describe a protocol to open the BBB by IA injection of hyperosmotic mannitol under the guidance of MRI in mice. The procedures (from preoperative preparation to postoperative care) can be completed within ~1.5 h, and the skill level required is on par with the induction of middle cerebral artery occlusion in small animals. This MRI-guided BBB opening technique in mice can be utilized to study the biology of the BBB and improve the delivery of various therapeutic agents to the brain.

2D Measurements of the Angle of the Vestibular Aqueduct Using CT Imaging.

Recently, Bächinger et al. developed a software that measures the angle between the vestibular aqueduct proximal to the vestibule and the distal vestibular aqueduct on computed tomography (CT) scans and found differences in the vestibular aqueduct angle between the hypoplastic and degenerative categories of Meniere's disease (MD). Hypoplastic radiological findings were associated with the development of bilateral MD and hypoplastic changes were not found outside of fetal temporal bones and individuals with MD. The purpose of this study is to examine how the software developed by Bächinger et al. performs when applied to a large dataset of adult patients with varied otologic diagnoses. Adult patients who underwent high resolution flat panel CT scans without intravenous contrast (n = 301) were retrospectively reviewed. Measurements of the angle of the vestibular aqueduct were made using the previously developed software tool. The tool could be applied to measure the vestibular aqueduct angle in most CT scans of the temporal bones (n = 572 ears, 95%). While the majority of ears fell within the normal range of <120 degrees (n = 462, 80%), fourteen ears (2.3%) in 13 patients were found to have vestibular aqueduct angles that meet criteria for hypoplastic MD (>140 degrees). Only one of the 13 patients had a diagnosis of MD and not in the ear in the hypoplastic category. An inconsistent pattern of other otologic diagnoses were found among the 13 individuals meeting criteria for hypoplastic MD. Although prior reports indicate the software has prognostic value in individuals with MD, these results suggest that the software may have lower positive predictive value when applied to a large population of individuals with varied otologic diagnoses.

Deuterium oxide as a contrast medium for real-time MRI-guided endovascular neurointervention.

Rationale: Endovascular intervention plays an important role in the treatment of various diseases, in which MRI-guidance can potentially improve precision. However, the clinical applications of currently available contrast media, including Gadolinium-based contrast agents and superparamagnetic iron oxide particles (SPIO), are hindered by safety concerns. In the present study, we sought to develop D2O as a novel contrast agent for guiding endovascular neurointervention. Methods: Animal studies were approved by institutional ACUC and conducted using an 11.7 T Bruker Biospec system and a 3T Siemens Trio clinical scanner for rodent and canine imaging, respectively. The locally selective blood brain barrier opening (BBBO) in rat brains was obtained by intraarterial (IA) injection of mannitol. The dynamic T2w* EPI MRI sequence was used to study the trans-catheter perfusion territory by IA administered SPIO before mannitol administration, whereas a dynamic T1w FLASH sequence was used to acquire Gd contrast-enhanced MRI for assessing BBBO after injection of mannitol. The contrast generated by D2O assessed by either EPI or FLASH methods was compared with the corresponding results assessed by SPIO or Gd. The utility of D2O MRI was also demonstrated to guide drug delivery to glioma in a mouse model. Finally, the clinical utility of D2O-MRI was demonstrated in a canine model. Results: Our study has shown that the contrast generated by D2O can be used to precisely delineate trans-catheter perfusion territory in both small and large animals. The perfusion territories determined by D2O-MRI show moderate correlation with those by SPIO-MRI (Spearman coefficient r = 0.5234, P < 0.001). Moreover, our results show that the perfusion territory determined by D2O-MRI can successfully predict the areas with BBBO after mannitol treatment similar to that assessed by Gd-MRI (Spearman coefficient r = 0.6923, P < 0.001). Using D2O-MRI as imaging guidance, the optimal infusion rate in the mouse brain was determined to be 150 µL/min to maximize the delivery efficacy to the tumor without serious off-target delivery to the brain parenchyma. The enhanced drug delivery of antibodies to the brain tumor was confirmed by fluorescence imaging. Conclusion: Our study demonstrated that D2O can be used as a negative MRI contrast medium to guide endovascular neurointervention. The established D2O -MRI method is safe and quantitative, without the concern of contrast accumulation. These qualities make it an attempting approach for a variety of endovascular procedures.

Endovascular therapy for acute stroke in children: age and size technical limitations.

Endovascular therapies for acute childhood stroke remain controversial and little evidence exists to determine the minimum age and size cut-off for thrombectomy in children. Despite this, an increasing number of reports suggest feasibility of thrombectomy in at least some children by experienced operators. When compared with adults, technical modifications may be necessary in children owing to differences in vessel sizes, tolerance of blood loss, safety of contrast and radiation exposure, and differing stroke etiologies. We review critical considerations for neurologists and neurointerventionalists when treating pediatric stroke with endovascular therapies. We discuss technical factors that may limit feasibility of endovascular therapy, including size of the femoral and cervicocerebral arteries, which contributes to vasospasm risk. The risk of femoral vasospasm can be assessed by comparing catheter outer diameter with estimated femoral artery size, which can be estimated based on the child's height. We review evidence supporting specific strategies to mitigate cervicocerebral arterial injury, including technique (stent retrieval vs direct aspiration) and device size selection. The importance of and strategies for minimizing blood loss, radiation exposure, and contrast administration are reviewed. Attention to these technical limitations is critical to delivering the safest possible care when thrombectomy is being considered for children with acute stroke.

New Mechanistic Insights, Novel Treatment Paradigms, and Clinical Progress in Cerebrovascular Diseases.

The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress.

Mid-term assessment of transverse sinus stent patency in 104 patients treated for intracranial hypertension secondary to dural sinus stenosis.

BACKGROUND: Transverse sinus (TS) stenting is a valid treatment alternative for patients with intracranial hypertension caused by underlying bilateral TS stenoses. Its mid-term patency has, however, not been well documented. OBJECTIVE: To assess the 6-month patency of TS stenting using subtracted CT venography (CTV). METHODS: A retrospective analysis of a prospectively collected database of patients undergoing TS stenting was performed. The cohort was a single-center, single-operator series of 125 consecutive patients treated between 2008 and 2018. Mid-term follow-up 320-row detector CTV was available for review in 104 patients. RESULTS: Follow-up CTV was obtained on average 6 months after stenting. Stents in all patients (100%) were patent. Subtracted reconstructions showed no intraluminal thrombus or neointimal hyperplasia. Native reconstructions confirmed the structural integrity of the stents. De novo stenosis proximal to the stent was noted in 10 cases (10%). A total of 10 patients (10%) received additional treatment due to recurrent symptoms. In univariate analysis, both high body mass index and stent size (>6 mm) were associated with development of de novo stenoses: OR 1.12 (95% CI 1.01 to 1.25, p=0.037) and OR 5.63 (95% CI 1.16 to 27.22, p=0.032), respectively. In multivariate analysis, only stent size (>6 mm) remained significant: OR 7.19 (95% CI 1.03 to 50.01, p=0.046). CONCLUSION: TS stenting is an effective treatment for intracranial hypertension secondary to dural sinus stenosis in an appropriately selected patient population. A 320-row dynamic CTV is a high-quality non-invasive imaging method that can assess both the physical integrity of the stent and its patency. At mid-term follow-up, all imaged stents were patent. The occurrence of de novo stenoses proximal to the stent (10%) correlated with stent size (>6 mm).

Interventional neuro-oncology.

Interventional neuro-oncology encompasses an array of image-guided therapies-intra-arterial chemotherapy, regional drug delivery, chemoembolization, tumor ablation-along with techniques to improve therapy delivery such as physical or chemical blood-brain barrier disruption and percutaneous catheter placement. Endovascular and percutaneous image-guided approaches to the treatment of the brain, eye, and other head and neck tumors will be discussed.

Mechanical Thrombectomy for Acute Ischemic Stroke: Considerations in Children.

The use of mechanical thrombectomy for the treatment of acute childhood arterial ischemic stroke with large vessel occlusion is increasing, with mounting evidence for its feasibility and safety. Despite this emerging evidence, clear guidelines for patient selection, thrombectomy technique, and postprocedure care do not exist for the pediatric population. Due to unique features of stroke in children, neurologists and interventionalists must consider differences in patient size, anatomy, collateral vessels, imaging parameters, and expected outcomes that may impact appropriate patient selection and timing criteria. In addition, different causes of stroke and comorbidities in children must be considered and may alter the safety and efficacy of thrombectomy. To optimize the success of endovascular intervention in children, a multidisciplinary team should take into account these nuanced considerations when determining patient eligibility, developing a procedural approach, and formulating a postprocedure neurological monitoring and therapeutic plan.

Removal of Antiscatter Grids for Spinal Digital Subtraction Angiography: Dose Reduction without Loss of Diagnostic Value.

Background Spinal digital subtraction angiography (DSA) exposes patients and operators to substantial amounts of radiation. Antiscatter grid (ASG) removal is used to decrease radiation exposure but may reduce image quality. Purpose To determine whether ASG removal during spinal DSA in adults reduces radiation dose while maintaining diagnostic image quality and whether dose reduction is related to body mass index (BMI). Materials and Methods This Health Insurance Portability and Accountability Act-compliant prospective study included adults undergoing spinal DSA between January and December 2016. Each procedure included an additional angiographic acquisition performed twice, once with and once without ASG, either documenting the artery of Adamkiewicz (no pathology group) or the condition leading to the procedure (pathology group). Dose differences between study acquisitions and the influence of BMI were evaluated via paired t test. Two neurointerventionalists blinded to acquisition protocols were asked to independently evaluate a sample of 40 study acquisitions (20 with ASG, 20 without ASG) from 20 randomly selected participants to (a) rate image quality, (b) categorize findings, and (c) determine whether images had been obtained with or without ASG. Percentage agreement on image quality, findings categorization, and ability to correctly identify the acquisition protocol was calculated for both readers. Results Fifty-three participants (mean age ± standard deviation, 51 years ± 15.2; 32 men) were evaluated. ASG removal reduced the mean dose per acquisition by approximately 33% (mean dose-area product and air kerma decreased from 202 to 135.6 µGy/m2 and from 35.3 to 24 mGy, respectively; P < .001) independently of BMI (P = .3). Both readers evaluated all images (40 of 40) as being of diagnostic quality and correctly categorized findings in 19 of 20 (95%) cases. Overall percentage agreement for correct protocol identification was 60% (12 of 20) for grid-in and 45% (nine of 20) for grid-out images. Conclusion Antiscatter grid removal during spinal digital subtraction angiography decreased participants' radiation exposure while preserving diagnostic image quality. © RSNA, 2020.

Atlanto-occipital ligament calcification: a novel imaging finding in pediatric rotational vertebral artery occlusion.

We describe a 2-year-old girl with bow hunter syndrome complicated by vertebral artery dissection and multiple ischemic infarcts. Pediatric bow hunter syndrome is a rare and likely under-recognized disorder. Interestingly, our patient had atlanto-occipital ligament calcification on CT scan, an imaging finding that has not been reported in association with bow hunter syndrome and one that might help increase recognition of this dynamic disorder of the posterior circulation.

Optimization of osmotic blood-brain barrier opening to enable intravital microscopy studies on drug delivery in mouse cortex.

Intra-arterial (IA) infusion of mannitol induces osmotic blood-brain barrier opening (OBBBO) and that method has been used for decades to improve drug delivery to the brain. However, high variability of outcomes prevented vast clinical adoption. Studies on dynamic multi-scale imaging of OBBBO as well as extravasation of IA injected therapeutic agents are essential to develop strategies assuring precision and reproducibility of drug delivery. Intravital microscopy is increasingly used to capture the dynamics of biological processes at the molecular level in convenient mouse models. However, until now OBBBO has been achieved safely in subcortical structures, which prevented direct insight into the process of extravasation through the skull window. Here, we used our previously developed real-time MRI to adjust the procedure to achieve robust cortical OBBBO. We found that catheter-mediated delivery to the cortex from the ipsilateral carotid artery can be improved by temporarily occluding the contralateral carotid artery. The reproducibility and safety of the method were validated by MRI and histology. This experimental platform was further exploited for studying with intravital microscopy the extravasation of 0.58 kDa rhodamine and 153 kDa anti-VEGF monoclonal antibody (bevacizumab) upon IA injection. Dynamic imaging during IA infusion captured the spatiotemporal dynamic of infiltration for each molecule into the brain parenchyma upon OBBBO. Small-sized rhodamine exhibited faster and higher penetration than the antibody. Histological analysis showed some uptake of the monoclonal antibody after IA delivery, and OBBBO significantly amplified the extent of its uptake. For quantitative assessment of cortical uptake, bevacizumab was radiolabeled with zirconium-89 and infused intraarterially. As expected, OBBBO potentiated brain accumulation, providing 33.90 ± 9.06% of injected dose per gram of brain tissue (%ID/g) in the cortex and 17.09 ± 7.22%ID/g in subcortical structures. In contrast IA infusion with an intact BBB resulted in 3.56 ± 1.06%ID/g and 3.57 ± 0.59%ID/g in the same brain regions, respectively. This study established reproducible cortical OBBBO in mice, which enabled multi-photon microscopy studies on OBBBO and drug targeting. This approach helped demonstrate in a dynamic fashion extravasation of fluorescently-tagged antibodies and their effective delivery into the brain across an osmotically opened BBB.