Arterioectatic Spinal Angiopathy of Childhood: Clinical, Imaging, Laboratory, Histologic, and Genetic Description of a Novel CNS Vascular Pathology.

Pediatric patients with myelopathy expressing intradural spinal vascular ectasia without arteriovenous shunting were studied at four tertiary referral neuropediatric centers. Patients were identified by retrospective review of institutional records and excluded if spinal vascular pathology could be classified into a previously described category of spinal vascular malformation. Four patients meeting the study criteria were enrolled in the study. Clinical, magnetic resonance imaging, catheter-directed angiography, laboratory, histological and genetic data were analyzed to characterize the disease process and elucidate underlying pathomechanisms. Our study revealed a highly lethal, progressive multi-segmental myelopathy associated with a unique form of non-inflammatory spinal angiopathy featuring diffuse enlargement and tortuosity of spinal cord arteries, spinal cord hyperemia, and spinal cord edema (Arterioectatic Spinal Angiopathy of Childhood). The condition was shown to mimic venous congestive myelopathy associated with pediatric spinal cord arteriovenous shunts on MRI but to have distinct pathognomonic findings on catheter-directed angiography. Clinicopathological, genetic, and neuroimaging features, which are described in detail, closely overlap with those of mitochondrial disease.

Correlation of Technical and Adjunctive Factors with Quantitative Tumor Reduction in Children Undergoing Selective Ophthalmic Artery Infusion Chemotherapy for Retinoblastoma.

BACKGROUND AND PURPOSE: Selective ophthalmic artery infusion chemotherapy has improved ocular outcomes in children with retinoblastoma. Our aim was to correlate quantitative tumor reduction and dichotomous therapeutic response with technical and adjunctive factors during selective ophthalmic artery infusion chemotherapy for retinoblastoma. An understanding of such factors may improve therapeutic efficacy. MATERIALS AND METHODS: All patients with retinoblastoma treated by selective ophthalmic artery infusion chemotherapy at a single center during a 9-year period were reviewed. Only first-cycle treatments for previously untreated eyes were studied. Adjunctive factors (intra-arterial verapamil, intranasal oxymetazoline external carotid balloon occlusion) and technical factors (chemotherapy infusion time, fluoroscopy time) were documented by medical record review. Quantitative tumor reduction was determined by blinded comparison of retinal imaging acquired during examination under anesthesia before and 3-4 weeks after treatment. The dichotomous therapeutic response was classified according to quantitative tumor reduction as satisfactory (≥ 50%) or poor (<50%). RESULTS: Twenty-one eyes met the inclusion criteria. Patients ranged from 2 to 59 months of age. Adjuncts included intra-arterial verapamil in 15, intranasal oxymetazoline in 14, and external carotid balloon occlusion in 14. Quantitative tumor reduction ranged from 15% to 95%. Six showed poor dichotomous therapeutic response. A satisfactory dichotomous therapeutic response was correlated with intra-arterial verapamil (P = .03) in the aggregate cohort and in a subgroup undergoing treatment with single-agent melphalan at a dose of <5 mg (P = .02). In the latter, higher average quantitative tumor reduction correlated with intra-arterial verapamil (P < .01). CONCLUSIONS: Intra-arterial verapamil during selective ophthalmic artery infusion chemotherapy is correlated with an improved therapeutic response, particularly when treating with lower doses of single-agent melphalan.

The Complex Spine in Children with Spinal Muscular Atrophy: The Transforaminal Approach-A Transformative Technique.

BACKGROUND AND PURPOSE: Spinal muscular atrophy, a genetic disease resulting in loss of motor function, presents from in utero to adulthood. Depending on progression and secondary scoliosis, spinal stabilization may be necessary. When planning intrathecal access in these patients, spinal anatomy is the most important factor. Therefore, when planning intrathecal nusinersen injections, we subdivided patients with spinal muscular atrophy into simple-versus-complex spine subgroups. Our purpose was to present our experience with our first 42 transforaminal intrathecal nusinersen injections. MATERIALS AND METHODS: We reviewed 31 consecutive patients with spinal muscular atrophy types 1-3 who presented for intrathecal nusinersen injections from March 2017 to September 2018. Nine children had complex spines (ie, spinal instrumentation and/or fusion) and required preprocedural imaging for route planning for subarachnoid space access via transforaminal or cervical approaches. RESULTS: A total of 164 intrathecal nusinersen injections were performed in 31 children 4-226 months of age, with 100% technical success in accessing the subarachnoid space. Nine patients with complex spinal anatomy underwent 45 intrathecal nusinersen injections; 42 of 45 procedures were performed via a transforaminal approach with the remaining 3 via cervical techniques. There were no complications. CONCLUSIONS: Our initial experience has resulted in a protocol-driven approach based on simple or complex spinal anatomy. Patients with simple spines do not need preprocedural imaging or imaging-guided intrathecal nusinersen injections. In contrast, the complex spine subgroup requires preprocedural imaging for route planning and imaging guidance for therapy, with the primary approach being the transforaminal approach for intrathecal nusinersen injections.

Calcifications associated with pediatric intracranial arterial aneurysms: incidence and correlation with pathogenetic subtypes.

BACKGROUND AND PURPOSE: Little is known about calcifications associated with pediatric intracranial arterial aneurysms (IAA). We sought to characterize calcifications associated with pediatric IAA according to aneurysm pathogenetic subtype. MATERIALS AND METHODS: Patients with IAA less than 20 years of age were retrospectively identified. Three fellowship-trained neuroradiologists independently reviewed each patient's CT studies for calcifications of the parent artery or aneurysm. Aneurysmal calcification (ANC) was correlated with characteristics of the patient (age, sex) and aneurysm pathogenetic subtype, size, morphology, rupture status, and location. RESULTS: Thirty-three patients (mean age 10 years) with 43 IAA were analyzed. There were no parent artery calcifications. Nine IAA were calcified. IAA in children with non-hemodynamic risk factors (arteriopathy, trauma, infection, tumor) were more commonly calcified than idiopathic IAA (p = 0.029). More than one third of the pediatric IAAs in this group (arteriopathy, infection trauma, tumor) were calcified. IAA ≥ 10 mm were more likely to be calcified (p = 0.03). IAA that were ruptured at presentation were less likely to be calcified (p = 0.03). ANC was not significantly associated with patient age (≤10 years vs. >10 years), sex, morphology (fusiform vs. saccular) or location (anterior vs. posterior circulation). CONCLUSION: Aneurysmal but not parent artery calcifications are associated with a significant minority of pediatric IAA. Pediatric ANCs are associated with underlying non-hemodynamic vascular risk factors (arteriopathy, infection, trauma, and tumor), size ≥10 mm and non-hemorrhagic presentation.

Endovascular therapy of acute ischemic stroke: report of the Standards of Practice Committee of the Society of NeuroInterventional Surgery.

OBJECTIVE: To summarize and classify the evidence for the use of endovascular techniques in the treatment of patients with acute ischemic stroke. METHODS: Recommendations previously published by the American Heart Association (AHA) (Guidelines for the early management of adults with ischemic stroke (Circulation 2007) and Scientific statement indications for the performance of intracranial endovascular neurointerventional procedures (Circulation 2009)) were vetted and used as a foundation for the current process. Building on this foundation, a critical review of the literature was performed to evaluate evidence supporting the endovascular treatment of acute ischemic stroke. The assessment was based on guidelines for evidence based medicine proposed by the Stroke Council of the AHA and the University of Oxford, Centre for Evidence Based Medicine (CEBM). Procedural safety, technical efficacy and impact on patient outcomes were specifically examined.

Society of NeuroInterventional Surgery Standards of Practice: general considerations.

This is the first in a set of documents intended to standardize techniques, procedures, and practices in the field of endovascular surgical neuroradiology. Standards are meant to define core practices for peer review, comparison, and improvement. Standards and guidelines also form the basic dialogue, reporting, and recommendations for ongoing practices and future development.

Good clinical outcome after ischemic stroke with successful revascularization is time-dependent.

BACKGROUND: Trials of IV recombinant tissue plasminogen activator (rt-PA) have demonstrated that longer times from ischemic stroke symptom onset to initiation of treatment are associated with progressively lower likelihoods of clinical benefit, and likely no benefit beyond 4.5 hours. How the timing of IV rt-PA initiation relates to timing of restoration of blood flow has been unclear. An understanding of the relationship between timing of angiographic reperfusion and clinical outcome is needed to establish time parameters for intraarterial (IA) therapies. METHODS: The Interventional Management of Stroke pilot trials tested combined IV/IA therapy for moderate-to-severe ischemic strokes within 3 hours from symptom onset. To isolate the effect of time to angiographic reperfusion on clinical outcome, we analyzed only middle cerebral artery and distal internal carotid artery occlusions with successful reperfusion (Thrombolysis in Cerebral Infarction 2-3) during the interventional procedure (<7 hours). Time to angiographic reperfusion was defined as time from stroke onset to procedure termination. Good clinical outcome was defined as modified Rankin Score 0-2 at 3 months. RESULTS: Among the 54 cases, only time to angiographic reperfusion and age independently predicted good clinical outcome after angiographic reperfusion. The probability of good clinical outcome decreased as time to angiographic reperfusion increased (unadjusted p = 0.02, adjusted p = 0.01) and approached that of cases without angiographic reperfusion within 7 hours. CONCLUSIONS: We provide evidence that good clinical outcome following angiographically successful reperfusion is significantly time-dependent. At later times, angiographic reperfusion may be associated with a poor risk-benefit ratio in unselected patients.

De novo cerebral arteriovenous malformation: case report and literature review.

We describe a rare case of a de novo cerebral arteriovenous malformation (AVM) in a 9-year-old girl. MR imaging at 6 years of age demonstrated band heterotopia. Follow-up MR imaging 3 years later demonstrated a new 3.5-cm AVM in the left parietol-occipital region, confirmed by conventional angiography. This report, along with limited previous reports, suggests that AVMs can be acquired lesions and that AVM development is a dynamic process extending into the postnatal period.

Microscopic computed tomography imaging of the cerebral circulation in mice: feasibility and pitfalls.

This study evaluates the utility and practical limitations of microcomputerized X-ray tomography (CT) as a research tool for examination of the cerebral circulation in mice. Six micro CT angiograms of the circle of Willis (COW) from six mice were obtained by scanning whole head and brain specimen perfused with a radio-opaque silicone contrast agent. Two-dimensional volume rendered images were postprocessed from three-dimensional image datasets using a partially automated high-throughput model that generated 10 surface projections for each specimen. The image processing model employed a straightforward global thresholding and computerized component labeling software algorithm. Postprocessed images were analyzed and results correlated with microdissection. Micro CT demonstration of COW vessels and their branch anatomy was assessed. 71% of COW vessels were completely demonstrated, 26% were partially demonstrated, and 3% were not demonstrated. All cases of nondemonstration and most cases of partial demonstration resulted from scan coverage or postprocessing clip error. Thresholding effect caused pseudostenosis of 8% of COW vessels and accounted for a minority of partial demonstration cases. No imaging artifacts were caused by contrast extravasation or ineffective contrast perfusion. Volume averaging caused minor angioarchitectural distortion of 58% of COW vessels. Ninety-five percent of COW > or =50 microm and 52% of COW vessels <50 microm were correctly identified by micro CT. Micro CT of the murine COW using a high-throughput image processing model is feasible. Angioarchitectural distortion due to volume averaging and thresholding effect can occur and pathological findings should be confirmed.

Eye position information on CT increases the identification of acute ischemic hypoattenuation.

BACKGROUND AND PURPOSE: It is possible that identification of eye deviation may sensitize a scan reader to early brain hypodensity associated with an arterial occlusive process. Our aim was to investigate the value of observing eye deviation on blinded CT identification of early hypoattenuation following ischemic infarct. MATERIALS AND METHODS: Two staff and 2 fellow neuroradiologists reviewed 75 brain CT scans obtained within 3 hours of acute ischemia from subjects in the Interventional Management of Stroke Study. Films were reviewed 3 months apart, the first time with tape over the eyes on the images, the second with the eyes visible. Readers were asked if early hypoattenuation in the middle cerebral artery (MCA) distribution or if a hyperattenuated MCA was present. kappa statistics were calculated to determine agreement among the 4 readers and between each of the 2 readings by the same reader, not only for the original interpretation of the blinded study neuroradiologist but also for the Alberta Stroke Program Early CT Score (ASPECTS) for each subject assigned by an unblinded expert panel. A generalized estimating equations modeling approach was used to look at the overall effect of including eye information for agreement between interpretations. RESULTS: Eye information availability was associated with improved agreement for detection of early ischemic hypoattenuation not only among the 4 readers but also between the 4 readers and both the blinded study neuroradiologist (P = .02) and the unblinded expert ASPECTS panel. When comparing first and second readings for hypoattenuation, we also noted increased mean values for sensitivity (46.8% first, 56.5% second), specificity (78.2%, 80.2%), positive predictive value (72.0%, 80.7%), negative predictive value (55.5%, 61.0%), and percentage agreement (61.0%, 67.5%). CONCLUSION: Observation of CT eye deviation significantly improves reader identification of acute ischemic hypoattenuation.

Efficient transmicrocatheter delivery of functional fibroblasts with a bioengineered collagen gel-platinum microcoil complex: toward the development of endovascular cell therapy for cerebral aneurysms.

BACKGROUND AND PURPOSE: Endoaneurysmal implantation of fibroblasts may promote healing of aneurysms and reduce recanalization after therapeutic embolization. The purpose of our study was to develop a device for delivery of fibroblasts with use of current microcoil technology. MATERIALS AND METHODS: Cell carrier devices and cell-free devices were fabricated by associating collagen gels (with or without fibroblasts) with platinum microcoils. During the propagation of control cell carrier devices for 1 week in culture, cell-mediated gel contraction (CMGC) occurred. Modified cell carrier devices created by glutaraldehyde cross-linking, ascorbate coculture, or extended CMGC were also characterized in vitro. Devices were deployed through microcatheters (533 microm lumen, 160 cm length). Gel retention, cell retention, cell death, and the ability to support local cell migration were analyzed in vitro. RESULTS: Cell viability was reduced by glutaraldehyde cross-linking but not by microcatheter transit. During microcatheter transit, cell carrier devices liberated minimal particulate matter and cellular DNA. Liberated particulate matter was reduced by glutaraldehyde cross-linking (P < .05) and extended CMGC (P < .04). Only cell carrier devices treated with glutaraldehyde cross-linking did not exhibit cell migration after microcatheter transit. Passage of cell-free devices through microcatheters sheared off most of their collagen gel. CONCLUSION: Collagen gel-platinum microcoil complexes can mediate efficient transmicrocatheter delivery of viable, migration-capable fibroblasts. CMGC is a necessary component of the process of gel stabilization that enables successful microcatheter transit. Although extended CMGC and glutaraldehyde cross-linking enhance gel stabilization, glutaraldehyde cross-linking decreases cell viability and migratory potential.

Basilar artery stent angioplasty for symptomatic intracranial athero-occlusive disease: complications and late midterm clinical outcomes.

BACKGROUND AND PURPOSE: After an initial series of basilar artery stent angioplasty indicated a high technical success rate and minimal morbidity, subsequent reports suggested significant procedural risks. We retrospectively reviewed our experience with basilar artery stent placement to assess complications and clinical outcomes. MATERIALS AND METHODS: Ten consecutive patients with symptomatic intracranial athero-occlusive disease underwent stent placement of the basilar artery at our institution (1999-2003). We collected clinical data by chart review and determined outcomes (modified Rankin Scale [mRS]) by telephone interview. Angiographic data were analyzed by 2 blinded investigators. Clinical and angiographic variables were tested for correlation with outcome and complications using the Pearson correlation test. RESULTS: Of 10 patients (mean follow-up time, 31 months), 4 patients suffered 6 ischemic complications that were immediate in 1, early delayed (<2 weeks) in 4, and late delayed (>2 weeks) in 1. Complications included basilar artery rupture in 1 patient, access site complications in 1 patient, and other non-neurologic complications in 5. Symptomatic restenosis occurred in 1 patient. Outcomes (mRS) were excellent (0-2) in 5 patients, good (3) in 4, and poor (4-6) in 1 patient, who died. Ischemic complications were associated with lesion lumen 45 degrees (P<.05). Less favorable clinical outcomes were associated with few ischemic complications and the presence of fewer than 2 patent vertebral arteries (P<.05). CONCLUSIONS: Despite a significant incidence of ischemic and nonischemic complications after basilar artery stent placement, most patients in this small series achieved freedom from vertebrobasilar ischemia and good to excellent clinical outcomes at late midterm follow-up (12-46 months). Ischemic complications usually had an early delayed presentation and procedural risks correlated with lesion characteristics.

Effects of endothelial injury on the rate of thrombus organization in canine carotid arteries occluded with microcoils.

SUMMARY: Thrombus organization in canine carotid arteries occluded with platinum microcoils was studied to determine if endothelial injury created with a Xenon Chloride Excimer Laser (XEL) could acclerate endovascular fibrosis. Ten common carotid artery stumps were created in ten dogs. Each of four stumps were schematically divided into four longitudinally contiguous injury zones (thermal ablation injury, non-ablative injury, proximal and distal non-injury zones) to test the effects of ablative and non-ablative injury and to establish a set of internal controls that would account for proximity to circulating blood at the ostium of the occluded artery. Following XEL irradiation of the endothelium through an arteriotomy, each stump was embolized with microcoils. Four control stumps were subjected to sham laser procedures, and embolized in an identical fashion. Two additional stumps were embolized in the absence of sham surgery. Angiographic, gross and histologic analysis was performed after four weeks. Specimens of freshly clotted whole blood mixed with microcoils were used as an additional control. In irradiated stumps and non-irradiated stumps (sham and embolization only), angiography revealed no evidence of coil compaction or recanalization. In all irradiated stumps the thermal ablation zone contained fibrous tissue and neovascularity without unorganized thrombus. The other zones in the irradiated stumps were indistingnishable from each other and from all zones in the non-irradiated sham stumps, containing primarily unorganized thrombus. Stumps embolized in the absence of sham surgery were filled with material that was grossly and microscopically identical to specimens of freshly clotted whole blood containing microcoils. The results indicate that thermal ablation injury of the endothelium accelerates thrombus organization in canine carotid arteries occluded with platinum microcoils.

In vitro effects of transcatheter injection on structure, cell viability, and cell metabolism in fibroblast-impregnated alginate microspheres.

PURPOSE: To determine if microsphere-encapsulated cell preparations can be delivered through a microcatheter without compromising microsphere structure, cell viability, or metabolism. MATERIALS AND METHODS: Fibroblast-impregnated microspheres were fabricated by using 1.0% alginate and rabbit synovial fibroblasts. Fibroblast-impregnated alginate microspheres injected through microcatheters were analyzed in parallel with identical noninjected microspheres. The effects of transcatheter injection on structure and cell viability (percentage of viable cells per microsphere) were correlated with microsphere size. Structural effects were analyzed by using light microscopy, and 7-day percentage (ratio of live cells to dead cells) cell viability was assessed with confocal microscopy and fluorescent staining. In a second series of experiments, the metabolism of small microspheres was studied during a course of 7 days by using a spectrophotometric bioanalyzer. RESULTS: Transcatheter injection caused fracturing and/or fragmentation of large (800-1,000 microm) and medium (500-750 microm) microspheres, while small (250-400 microm) microspheres were structurally unaffected by transcatheter injection. Fracturing and fragmentation were associated with cell release from the alginate matrix. Although transcatheter injection reduced cell viability by 17%-23% in all size categories, it did not cause a detectable alteration in the rate of glucose metabolism. CONCLUSION: Transcatheter injection was physiologically well tolerated by fibroblasts encapsulated in alginate microspheres; however, when microsphere diameter exceeded the catheter diameter, fracturing and fragmentation of microspheres compromised the sequestration function of the microsphere vector.

Prevention of complications resulting from endovascular carotid sacrifice: a retrospective assessment.

OBJECTIVE: To determine the protective effects of various periprocedural interventions in the prevention of cerebral ischemia as a complication of endovascular carotid sacrifice (ECS). METHODS: Thirty-two cases of ECS performed at our institution, between October 1987 and July 1998, were reviewed. Fifteen patients underwent superficial temporal artery-to-middle cerebral artery bypass surgery. In 21 patients, the carotid artery was occluded proximal to the target lesion; and in 11 patients, a lesion trapping procedure was performed. Six patients were prophylactically anticoagulated, 14 received antiplatelet agents prophylactically, and 12 received no pharmacoprophylaxis. RESULTS: Among the six patients who were anticoagulated, there were no embolic events. Embolic events affected 4 of 14 patients receiving prophylactic antiplatelet agents, 2 of 12 patients receiving no pharmacoprophylaxis, 1 of 11 patients who underwent a trapping procedure, and 5 of 21 patients whose carotid artery was occluded proximal to the target lesion. Postocclusion cerebral ischemia developed in 7 of 15 patients who underwent bypass surgery, and in 1 of the remaining 17. CONCLUSION: Superficial temporal artery-to-middle cerebral artery bypass did not protect against postocclusion cerebral ischemia after ECS in this series (P = 0.01). Although the small number of patients studied precludes statistical validity (P = 0.29), the trends suggest that antiplatelet agents provide no protection against postocclusion cerebral emboli after ECS. Prophylactic anticoagulation (P = 0.32) and lesion trapping (P = 0.12) may reduce the frequency of postocclusion embolic events after ECS; however, because of the small number of patients, statistical significance could not be demonstrated.

Timing of ICAM-I Expression in a Canine Model of Post-Haemorrhagic Cerebral Vasospasm.

SUMMARY: Temporal alterations in endothelial intercellular adhesion molecule I (ICAM-I) expression during the course of post-haemorrhagic cerebral vasospasm (PHCV) are correlated with angiographic and histologic changes in the canine basilar artery. Angiography was performed in six dogs to obtain baseline measurements of basilar artery diameter. In three dogs subarachnoid haemorrhage (SAH) was created by performing percutaneous puncture of the cisterna magna, and replacing 7 ml of cerebrospinal fluid with 7 ml of arterial blood. The remaining three dogs were used as controls. Daily angiography was performed on all dogs to determine the percent reduction in basilar artery diameter (%RBAD). One dog from each group was sacrificed after 24 hours. The remaining two dogs in each group were sacrificed after 48 hours. Each basilar artery was perfusion fixed and subjected to histologic, and immunohistochemical analysis. In the SAH group, the average %RBAD was 4 (+/- 3) at 24 hours, and 36 (+/- 1) at 48 hours. In the control group, the average %RBAD was - 1 (+/- 1) at 24 hours, and 0 (+/- 2) at 48 hours. Endothelial edema and endothelial expression of ICAM-I were found at 24 hours.At 48 hours post-SAH there was widespread endothelial desquamation, but no evidence of ICAM-I expression. In the control group, histology was normal and no ICAM-I expression was found at 24 or 48 hours. The results suggest that a brief window of therapeutic efficacy exists during the first postictal 24 hours where ICAM-I antagonists may be useful in suppressing the pathogenesis of PHCV.

Histologic and morphologic comparison of experimental aneurysms with human intracranial aneurysms.

PURPOSE: Vein pouch aneurysms are the most commonly created experimental lesions in neuroendovascular research. We sought to determine whether an experimental aneurysm that is derived from a pancreatic elastase-digested arterial sac (EDASA) models the histology and morphology of human cerebral aneurysms more accurately than the vein pouch aneurysm does. METHODS: EDASAs were created in the common carotid arteries of four rabbits, and vein pouch aneurysms were created in the common carotid arteries of four pigs. Five recently ruptured human cerebral aneurysms were obtained at autopsy. Identical histologic preparations were made for all specimens, and a vascular pathologist performed blinded histologic analyses. Morphologic dimensions were measured with a micrometer at 40-fold magnification. RESULTS: In each human cerebral aneurysm, there was complete absence of internal elastic lamina and tunica media, and none showed evidence of mural inflammation or neointimal proliferation. Average wall thickness was 51 microm. All vein pouch aneurysms had a well-developed internal elastic lamina and tunica media, and all exhibited profound inflammation and neointimal proliferation. Average wall thickness was 290 microm. EDASAs were devoid of internal elastic lamina, their tunica medias were mildly atrophic, and the sac walls contained only mild inflammation and neointimal proliferation. Average wall thickness was 46 microm. CONCLUSIONS: EDASAs model the morphologic and histologic characteristics of human cerebral aneurysms more accurately than vein pouch aneurysms do.