Fostering research in pediatric interventional radiology: needs assessment and suggestions for support.

BACKGROUND: Due to the rarity of pediatric diseases, collaborative research is the key to maximizing the impact of research studies. A research needs assessment survey was created to support initiatives to foster pediatric interventional radiology research. OBJECTIVE: To assess the status of pediatric interventional radiology research, identify perceived barriers, obtain community input on areas of research/education/support, and create metrics for evaluating changes/responses to programmatic initiatives. MATERIALS AND METHODS: A survey link was sent to approximately 275 members of the Society for Pediatric Interventional Radiology (SPIR) between May and October 2020. Data was collected using a web-based interface. Data collected included practice setting, clinical role, research experience, research barriers, and suggestions for future initiatives. RESULTS: Fifty-nine surveys were analyzed with a staff physician survey response rate of 28% (56/198). A wide range of practice sizes from 15 countries were represented. Respondents were predominantly staff physicians (95%; 56/59) with an average of 11 years (range: 1-25 years) of clinical experience working at academic or freestanding children's hospitals. A total of 100% (59/59) had research experience, and 70% (41/58) had published research with a mean of 30 peer-reviewed publications (range: 1-200). For job security, 56% (33/59) of respondents were expected or required to publish, but only 19% (11/58) had research support staff, and 42% (25/59) had protected research time, but of those, 36% (9/25) got the time "sometimes or never." Lack of support staff, established collaborative processes, and education were identified as top barriers to performing research. CONCLUSIONS: The needs assessment survey demonstrated active research output despite several identified barriers. There is a widespread interest within the pediatric interventional radiology community for collaborative research.

Efficacy of a prolonged stability melphalan formulation for intra-arterial treatment of retinoblastoma.

BACKGROUND: Melphalan, which is poorly soluble at room temperature, is widely used for the treatment of retinoblastoma by selective ophthalmic artery infusion. Evomela, a propylene glycol-free formulation of melphalan with improved solubility and stability, has recently been used as an alternative.To compare the safety and efficacy of Evomela with standard-formulation melphalan (SFM) in the treatment of retinoblastoma by selective ophthalmic artery infusion. METHODS: We performed a retrospective case-control study of patients with retinoblastoma undergoing selective ophthalmic artery infusion with SFM or Evomela at a single institution. Cycle-specific percent tumor regression (CSPTR) was estimated by comparing photos obtained during pretreatment examination under anesthesia (EUA) with those obtained during post-treatment EUA 3-4 weeks later. CSPTR, ocular salvage rates, complication rates, operation times (unadjusted and adjusted for difficulty of ophthalmic artery catheterization), and intraprocedural dose expiration rates were compared between Evomela- and SFM-treated groups. Univariate and multivariate analyses were performed. RESULTS: Ninety-seven operations (melphalan: 45; Evomela: 52) for 23 patients with 27 retinoblastomas were studied. The ocular salvage rate was 79% in the SFM-treated group and 69% in the Evomela-treated group. Multivariate regression controlling for tumor grade, patient age, and treatment history revealed no significant differences in ocular salvage rate, CSPTR, complication rates, or operation times. Although the dose expiration rate was higher for the SFM-treated group, the difference was not statistically significant. Notably, there were no ocular or cerebral ischemic complications. CONCLUSION: Evomela has non-inferior safety and efficacy relative to SFM when used for the treatment of retinoblastoma by selective ophthalmic artery infusion.

Rapid ventricular overdrive pacing and other advanced flow-control techniques for the endovascular embolization of vein of galen malformations.

Endovascular embolization is the primary strategy in the management for vein of Galen malformations (VOGM). However, despite significant advances in endovascular embolization technologies and techniques, VOGMs remain very technically challenging lesions largely due to the high-flow arteriovenous shunts present in these malformations. A variety of advanced flow-control techniques can be implemented to mitigate the risk of venous escape and increase the safety and efficacy of endovascular treatment. These techniques include regionally targeted strategies (transvenous embolization and balloon-assisted transarterial embolization) and global flow-control methods (pharmacologic cardiac arrest and rapid ventricular overdrive pacing). Each of these strategies are associated with unique advantages and disadvantages, highlighting the importance of a patient-specific approach when treating these challenging lesions.

Ocular survival after intra-arterial chemotherapy for retinoblastoma improves with accrual of experience and programmatic evolution.

BACKGROUND: Intra-arterial chemotherapy (IAC) for the treatment of intraocular retinoblastoma has gained recognition as a method to improve ocular salvage; however, there is a paucity of evidence supporting treatment factors prognosticating ocular survival. METHODS: All patients with retinoblastoma treated with IAC at a single institution between December 2008 and December 2019 were evaluated. Patient demographics, tumor classification, prior treatments, procedural data, other non-IAC therapies, adverse reactions, procedural complications, ocular outcomes, and overall survival were assessed via retrospective chart review. Factors suggestive of increased ocular survival were identified via univariate and multivariate analyses. The impact of accrued treatment experience was evaluated by grouping eyes by the respective year, IAC treatment was initiated. RESULTS: Forty-nine eyes of 43 patients were treated for retinoblastoma with IAC (256 total procedures). At least grade 3 neutropenia was observed following 19% of IAC procedures. The risk of neutropenia was not statistically different between single or multidrug IAC. Comparing those who received balloon-assisted intra-arterial chemotherapy (bIAC) in more than two-thirds of cycles to those who did not, the risk of arterial access site complications was not statistically different. Multivariate analysis revealed a significantly lower risk of enucleation associated with treatment era in years (hazard ratio [HR] = 0.52-1.00, p < .05) and laser therapies (HR = 0.02-0.60, p < .05). CONCLUSIONS: Ocular survival rates in patients treated with IAC for retinoblastoma at our institution have increased over time. Accrued treatment experience and programmatic changes have likely contributed. Larger, prospective series may lead to a better understanding of factors that consistently contribute to better ocular salvage.

Quantitative Electroencephalography After Pediatric Anterior Circulation Stroke.

OBJECTIVE: Regional differences were investigated in quantitative EEG (QEEG) characteristics and associations of QEEG to hemodynamics after pediatric acute stroke. METHODS: Quantitative EEG was analyzed, including power in delta, theta, alpha, and beta bands, alpha-delta power ratio, total power, and spectral edge frequency from 11 children with unilateral, anterior circulation strokes during the first 24 hours of continuous EEG recording. Differences between injured and uninjured hemispheres were assessed using multivariate dynamic structural equations modeling. Dynamic structural equations modeling was applied to six children with hemorrhagic stroke undergoing arterial blood pressure, heart rate, and cerebral oximetry monitoring to investigate associations between hemodynamics with QEEG adjacent to anterior circulation regions. RESULTS: All patients with acute ischemic stroke ( n = 5) had lower alpha and beta power and spectral edge frequency on injured compared with uninjured regions. This was not consistent after hemorrhagic stroke ( n = 6). All hemorrhagic stroke patients demonstrated negative association of total power with arterial blood pressure within injured regions. No consistency was observed for direction or strength of association in other QEEG measures to arterial blood pressure nor were such consistent relationships observed for any QEEG measure studied in relation to heart rate or cerebral oximetry. CONCLUSIONS: After pediatric anterior circulation acute ischemic stroke, reduced spectral edge frequency and alpha and beta power can be observed on injured as compared with noninjured regions. After pediatric anterior circulation hemorrhagic stroke, total power can be negatively associated with arterial blood pressure within injured regions. Larger studies are needed to understand conditions in which QEEG patterns manifest and relate to hemodynamics and brain penumbra.

Initial Diagnostic Evaluation of the Child With Suspected Arterial Ischemic Stroke.

ABSTRACT: Numerous factors make the initial diagnostic evaluation of children with suspected arterial ischemic stroke (AIS) a relatively unsettling challenge, even for the experienced stroke specialist. The low frequency of pediatric AIS, diversity of unique age-oriented stroke phenotypes, and unconventional approaches required for diagnosis and treatment all contribute difficulty to the process. This review aims to outline important features that differentiate pediatric AIS from adult AIS and provide practical strategies that will assist the stroke specialist with diagnostic decision making in the initial phase of care.

Definitive Diagnostic Evaluation of the Child With Arterial Ischemic Stroke and Approaches to Secondary Stroke Prevention.

ABSTRACT: In children with arterial ischemic stroke (AIS), the definitive diagnosis of stroke subtype and confirmation of stroke etiology is necessary to mitigate stroke morbidity and prevent recurrent stroke. The common causes of AIS in children are sharply differentiated from the common causes of adult AIS. A comprehensive, structured diagnostic approach will identify the etiology of stroke in most children. Adequate diagnostic evaluation relies on advanced brain imaging and vascular imaging studies. A variety of medical and surgical secondary stroke prevention strategies directed at the underlying cause of stroke are available. This review aims to outline strategies for definitive diagnosis and secondary stroke prevention in children with AIS, emphasizing the critical role of neuroimaging.

Reperfusion Therapies for Children With Arterial Ischemic Stroke.

ABSTRACT: Modern hyperacute reperfusion therapies including intravenous thrombolysis and mechanical thrombectomy have transformed the management of arterial ischemic stroke (AIS) in adults. Multiple randomized clinical trials have demonstrated that these therapies enable remarkable improvements in clinical outcome for properly selected patients with AIS. Because pediatric patients were excluded from predicate clinical trials, there is a conspicuous lack of data to guide selection of therapies and inform age-adjusted and pathology-oriented treatment modifications for children. Specifically, technical guidance concerning treatment eligibility, drug dosing, and device implementation is lacking. This review aims to outline important features that differentiate pediatric AIS from adult AIS and provide practical strategies that will assist the stroke specialist with therapeutic decision making.

Diminishing returns with successive device passes in mechanical thrombectomy for stroke.

BACKGROUND: Multiple device passes are associated with complications and poor functional outcomes following mechanical thrombectomy (MT) for emergent large vessel occlusion (ELVO). OBJECTIVE: To characterize the relationship between number of device passes, complications, angiographic outcomes, and clinical outcomes in MT for ELVO. METHODS: This is a single-center, retrospective cohort study. Individual device passes for MT were evaluated for any change in Thrombolysis in Cerebral Infarction (TICI) score, successful revascularization (TICI 2b or 3), and complications. Outcomes were compared among groups requiring multiple passes with various cut-off points. Risk factors for unfavorable clinical outcome [90 day modified Rankin Scale > 2] were assessed using multivariate analysis. RESULTS: Successful revascularization was achieved in 75% of 163 patients and 36% required only one device pass. After the second pass, the likelihood of angiographic improvement significantly decreased (p < 0.001). Using multiple cut-off points, higher post-procedural NIHSS scores, mortality rates, and unfavorable 90-day outcomes were associated with a greater number of passes. Multivariate analysis revealed ICA thrombus (comparison: M2, OR: 25, 95% CI 2-275, p = 0.01) and failed revascularization (OR: 68, 95% CI 3.12-1489, p = 0.01) as the only significant predictors of unfavorable clinical outcome. Nonetheless, the likelihood of favorable clinical outcome was higher in patients with an ICA occlusion who were revascularized in < 2 vs. ≥ 2 (44 vs 4%, p = 0.01) or < 3 vs. ≥ 3 (32 vs. 0%, p = 0.02) passes. CONCLUSION: The likelihood of angiographic improvement in patients with ELVO significantly decreases after the second pass. A greater number of passes is associated with worsened clinical outcomes.

Accelerated sonothrombolysis with Definity in a xenographic porcine cerebral thromboembolism model.

Adjuvant ultrasound at 2 MHz with or without an ultrasound contrast agent improves the rate of thrombus resolution by recombinant tissue plasminogen activator (rt-PA) in laboratory and clinical studies. A sub-megahertz approach can further expand this therapy to a subset of patients with an insufficient temporal bone window, improving efficacy in unselected patient populations. The aim of this study was to determine if a clinical ultrasound contrast agent (UCA), Definity, and 220 kHz pulsed ultrasound accelerated rt-PA thrombolysis in a preclinical animal model of vascular occlusion. The effect of Definity and ultrasound on thrombus clearance was first investigated in vitro and subsequently tested in a xenographic porcine cerebral thromboembolism model in vivo. Two different microcatheter designs (end-hole, multi-side-hole) were used to infuse rt-PA and Definity at the proximal edge or directly into clots, respectively. Sonothrombolysis with Definity increased clot mass loss relative to saline or rt-PA alone in vitro, only when rt-PA was administered directly into clots via a multi-side-hole microcatheter. Combined treatment with rt-PA, Definity, and ultrasound in vivo increased the rate of reperfusion up to 45 min faster than clots treated with rt-PA or saline. In this porcine cerebral thromboembolism model employing retracted human clots, 220 kHz ultrasound, in conjunction with Definity increased the probability of early successful reperfusion with rt-PA.

Cervicocerebral quantitative arterial tortuosity: a biomarker of arteriopathy in children with intracranial aneurysms.

OBJECTIVE: Although intracranial arterial aneurysms (IAAs) of childhood are usually idiopathic, it is possible that underlying arteriopathy escapes detection when using conventional diagnostic tools. Quantitative arterial tortuosity (QAT) has been studied as a biomarker of arteriopathy. The authors analyzed cervicocerebral QAT in children with idiopathic IAAs to assess the possibility of arteriopathy. METHODS: Cases were identified by text-string searches of imaging reports spanning the period January 1993 through June 2017. QAT of cervicocerebral arterial segments was measured from cross-sectional studies using image-processing software. Other imaging and clinical data were confirmed by retrospective electronic record review. Children with idiopathic IAAs and positive case controls, with congenital arteriopathy differentiated according to aneurysm status (with and without an aneurysm), were compared to each other and to healthy controls without vascular risk factors. RESULTS: Cervicocerebral QAT was measured in 314 children: 24 with idiopathic IAAs, 163 with congenital arteriopathy (including 14 arteriopathic IAAs), and 127 healthy controls. QAT of all vertebrobasilar segments was larger in children with IAAs (idiopathic and arteriopathic forms) (p < 0.05). In children with congenital arteriopathy without an aneurysm, QAT was decreased for the distal cervical vertebral arteries and increased for the supraspinal vertebral artery relative to healthy children. QAT of specific cervicocerebral segments correlated with IAA size and rupture status. CONCLUSIONS: Cervicocerebral QAT is a biomarker of arteriopathy in children with IAA, even in the absence of other disease markers. Additional findings suggest a correlation of cervicocerebral QAT with IAA size and rupture status and with the presence of IAA in children with congenital arteriopathy.

Effect of Clot Stiffness on Recombinant Tissue Plasminogen Activator Lytic Susceptibility in Vitro.

The lytic recombinant tissue plasminogen activator (rt-PA) is the only drug approved by the Food and Drug Administration for treating ischemic stroke. Less than 40% of patients with large vessel occlusions who are treated with rt-PA have improved blood flow. However, up to 6% of all patients receiving rt-PA develop intracerebral hemorrhage. Predicting the efficacy of rt-PA treatment a priori could help guide therapeutic decision making, such that rt-PA is administered only to those individuals who would benefit from this treatment. Clot composition and structure affect the lytic efficacy of rt-PA and have an impact on elasticity. However, the relationship between clot elasticity and rt-PA lytic susceptibility has not been adequately investigated. The goal of this study was to quantify the relationship between clot elasticity and rt-PA susceptibility in vitro. Human and porcine highly retracted and mildly retracted clots were fabricated in glass pipettes. The rt-PA lytic susceptibility was evaluated in vitro using the percent clot mass loss. The Young's moduli of the clots were estimated using ultrasound-based single-track-location shear wave elasticity imaging. The percent mass loss in mildly retracted porcine and human clots (28.9 ± 6.1% and 45.2 ± 7.1%, respectively) was significantly higher (p < 0.05) than in highly retracted porcine and human clots (10.9 ± 2.1% and 25.5 ± 10.0%, respectively). Furthermore, the Young's moduli of highly retracted porcine and human clots (5.33 ± 0.92 and 3.21 ± 1.97 kPa, respectively) were significantly higher (p < 0.05) than those of mildly retracted porcine and human clots (2.66 ± 0.55 and 0.79 ± 0.21 kPa, respectively). The results revealed an inverse relationship between the percent clot mass loss and Young's modulus. These findings motivate continued investigation of ultrasound-based methods to assess clot stiffness in order to predict rt-PA thrombolytic efficacy.

A comprehensive institutional overview of intrathecal nusinersen injections for spinal muscular atrophy.

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal-recessive neuromuscular disorder resulting in progressive muscle weakness. In December 2016, the U.S. Food and Drug Administration approved the first treatment for SMA, a drug named nusinersen (Spinraza) that is administered intrathecally. However many children with SMA have neuromuscular scoliosis or spinal instrumentation resulting in challenging intrathecal access. Therefore alternative routes must be considered in these complex patients. OBJECTIVE: To investigate routes of drug access, we reviewed our institutional experience of administering intrathecal nusinersen in all children with spinal muscular atrophy regardless of spinal anatomy or instrumentation. MATERIALS AND METHODS: We reviewed children with SMA who were referred for intrathecal nusinersen injections from March to December 2017 at our institution. In select children with spinal hardware, spinal imaging was requested to facilitate pre-procedure planning. Standard equipment for intrathecal injections was utilized. All children were followed up by their referring neurologist. RESULTS: A total of 104 intrathecal nusinersen injections were performed in 26 children with 100% technical success. Sixty procedures were performed without pre-procedural imaging and via standard interspinous technique. The remaining 44 procedures were performed in 11 complex (i.e. neuromuscular scoliosis or spinal instrumentation) patients requiring pre-procedural imaging for planning purposes. Nineteen of the 44 complex procedures were performed via standard interspinous technique from L2 to S1. Twenty-two of the 44 complex procedures were performed using a neural-foraminal approach from L3 to L5. Three of the 44 complex procedures were performed via cervical puncture technique. There were no immediate or long-term complications but there was one child with short-term complications of meningismus and back pain at the injection site. CONCLUSION: Although we achieved 100% technical success in intrathecal nusinersen administration, our practices evolved during the course of this study. As a result of our early experience we developed an algorithm to assist in promoting safe and effective nusinersen administration in children with spinal muscular atrophy regardless of SMA type, abnormal spinal anatomy and complex spinal instrumentation.

Genetic Determinants of Cerebral Arterial Adaptation to Flow-loading.

BACKGROUND: In animal models, flow-loading is a necessary and sufficient hemodynamic factor to express the Cerebral Aneurysm (CA) phenotype. Using a rat model, this study characterizes the molecular events that comprise the cerebral arterial response to flow-loading and reveals their significance relating to the CA phenotype. OBJECTIVE: To characterize the molecular events that underlie expansive remodeling of cerebral arteries in two genetically distinct inbred rat strains with differential susceptibility to flow-dependent cerebrovascular pathology. METHODS: Thirty-two rats underwent bilateral common carotid artery ligation (BCL) (n=16) or Sham Surgery (SS) (n=16). Nineteen days later, vertebrobasilar arteries were harvested, histologically examined and analyzed for mRNA and protein expression. Flow-induced changes in histology, mRNA and protein expression were compared between BCL and SS rats. Differences between aneurysm-prone (Long Evans, LE) and resistant (Brown Norway, BN) strains were evaluated. RESULTS: Basilar Artery (BA) medial thickness/luminal diameter ratio was significantly reduced in BCL rats, without significant differences between LE (2.02 fold) and BN (1.94 fold) rats. BCL significantly altered BA expression of mRNA and protein but did not affect blood pressure. Eight genes showed similarly large flow-induced expression changes in LE and BN rats. Twenty-six flow responsive genes showed differences in flow-induced expression between LE and BN rats. The Cthrc1, Gsta3, Tgfb3, Ldha, Myo1d, Ermn, PTHrp, Rgs16 and TRCCP genes showed the strongest flow responsive expression, with the largest difference between LE and BN rats. CONCLUSIONS: Our study reveals specific molecular biological responses involved in flow-induced expansive remodeling of cerebral arteries that may influence differential expression of flowdependent cerebrovascular pathology.

Severe carotid stenosis and delay of reperfusion in endovascular stroke treatment: an Interventional Management of Stroke-III study.

OBJECTIVE The impact of extracranial carotid stenosis on interventional revascularization of acute anterior circulation stroke is unknown. The authors examined the effects of high-grade carotid stenosis on the results of endovascular treatment of patients in the Interventional Management of Stroke (IMS)-III trial. METHODS The 278 patients in the endovascular arm of the IMS-III trial were categorized according to the degree of carotid stenosis as determined by angiography. In comparing patients with severe stenosis or occlusion (≥ 70%) to those without severe stenosis (< 70%), the authors evaluated the time to endovascular reperfusion, modified Thrombolysis in Cerebrovascular Infarction (mTICI) scores, 24-hour mean infarct volumes, symptomatic intracerebral hemorrhage rates, and modified Rankin Scale (mRS) scores at 90 days. RESULTS Compared with the 249 patients with less than 70% stenosis, patients with severe stenosis (n = 29) were found to have a significantly longer mean time to reperfusion (105.7 vs 77.7 minutes, p = 0.004); differences in mTICI scores, infarct volumes, hemorrhage rates, and mRS scores at 90 days did not reach statistical significance. Multiple regression analysis revealed that severe carotid stenosis (p < 0.0001) and higher baseline National Institutes of Health Stroke Scale (NIHSS) scores (p = 0.004) were associated with an increase in time to reperfusion. Older age (p < 0.0001), higher NIHSS score (p < 0.0001), and the absence of reperfusion (p = 0.001) were associated with worse clinical outcomes. CONCLUSIONS Severe ipsilateral ICA stenosis was associated with a significantly longer time to reperfusion in the IMS-III trial. Although these findings may not translate directly to modern devices, this 28-minute delay in reperfusion has significant implications, raising concern over the treatment of tandem ICA stenosis and downstream large-vessel occlusion.

Imaging patterns of venous-related brain injury in children.

Venous-related brain injury is a common form of cerebrovascular injury in children and encompasses a diverse group of cerebrovascular diagnoses. The purpose of this pictorial essay is to introduce the relevant anatomy, pathophysiology and various imaging patterns of venous-related cerebral injury in children. Unifying concepts to better understand the effects of venous hypertension in the developing brain will be emphasized. These unifying concepts will provide the imaging professional with a conceptual framework to better understand and confidently identify imaging patterns of venous-related cerebral injury.

The Interlenticulostriate Approach to Very High-Riding Distal Basilar Trunk Aneurysms.

BACKGROUND: Most high-riding distal basilar trunk aneurysms can be surgically approached via the transsylvian route and its orbitozygomatic variant. However, on rare occasions, the basilar bifurcation may be unusually high and an approach above the carotid terminus may be required. OBJECTIVE: In this cadaveric study, we sought to determine the feasibility and exposure limits of the interlenticulostriate approach (ILSA). METHODS: A standard transsylvian approach was performed in 10 cerebral hemispheres of 5 formalin-fixed, silicone-injected cadaver heads. The interpeduncular cistern was exposed via the opticocarotid window, carotid-oculomotor window, and supracarotid ILSA window. The latter was measured and an aneurysm clip or ventriculostomy stylet was placed as high as possible through each corridor. Using noncontrast 3-D rotational angiography, clip/stylet positions were measured relative to the dorsum sellae. RESULTS: ILSA provided a 9.4 × 4.6 mm mean surgical corridor, just enough room for a standard clip applier. This space was limited by the carotid bifurcation inferiorly, the lenticulostriate arteries medially and laterally, and the optic tract superiorly. There was no difference between opticocarotid and carotid-oculomotor windows, in terms of clip position (+8.9 vs +8.6 mm, respectively; P = .78). In contrast, ILSA provided significantly improved superior exposure, compared with either approaches (mean stylet position: +14.3 mm; P = .005). The exposure benefit afforded by ILSA was consistent across all 10 hemispheres, ranging from +2.5 to +8 mm. CONCLUSION: For high-riding distal basilar trunk aneurysms that cannot be reached via the frontotemporal orbitozygomatic approach, ILSA can provide a viable route of access. Vascular neurosurgeons should be familiarized with this approach.