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OBJECTIVE The role of endovascular treatment in the management of patients with brain arteriovenous malformations (AVMs) remains uncertain. AVM embolization can be offered as stand-alone curative therapy or prior to surgery or stereotactic radiosurgery (SRS) (pre-embolization). The Treatment of Brain AVMs Study (TOBAS) is an all-inclusive pragmatic study that comprises two randomized trials and multiple registries. METHODS Results from the TOBAS curative and pre-embolization registries are reported. The primary outcome for this report is death or dependency (modified Rankin Scale [mRS] score > 2) at last follow-up. Secondary outcomes include angiographic results, perioperative serious adverse events (SAEs), and permanent treatment-related complications leading to an mRS score > 2. RESULTS From June 2014 to May 2021, 1010 patients were recruited in TOBAS. Embolization was chosen as the primary curative treatment for 116 patients and pre-embolization prior to surgery or SRS for 92 patients. Clinical and angiographic outcomes were available in 106 (91%) of 116 and 77 (84%) of 92 patients, respectively. In the curative embolization registry, 70% of AVMs were ruptured, and 62% were low-grade AVMs (Spetzler-Martin grade I or II), while the pre-embolization registry had 70% ruptured AVMs and 58% low-grade AVMs. The primary outcome of death or disability (mRS score > 2) occurred in 15 (14%, 95% CI 8%–22%) of the 106 patients in the curative embolization registry (4 [12%, 95% CI 5%–28%] of 32 unruptured AVMs and 11 [15%, 95% CI 8%–25%] of 74 ruptured AVMs) and 9 (12%, 95% CI 6%–21%) of the 77 patients in the pre-embolization registry (4 [17%, 95% CI 7%–37%] of 23 unruptured AVMs and 5 [9%, 95% CI 4%–20%] of 54 ruptured AVMs) at 2 years. Embolization alone was confirmed to occlude the AVM in 32 (30%, 95% CI 21%–40%) of the 106 curative attempts and in 9 (12%, 95% CI 6%–21%) of 77 patients in the pre-embolization registry. SAEs occurred in 28 of the 106 attempted curative patients (26%, 95% CI 18%–35%, including 21 new symptomatic hemorrhages [20%, 95% CI 13%–29%]). Five of the new hemorrhages were in previously unruptured AVMs (n = 32; 16%, 95% CI 5%–33%). Of the 77 pre-embolization patients, 18 had SAEs (23%, 95% CI 15%–34%), including 12 new symptomatic hemorrhages [16%, 95% CI 9%–26%]). Three of the hemorrhages were in previously unruptured AVMs (3/23; 13%, 95% CI 3%–34%). CONCLUSIONS Embolization as a curative treatment for brain AVMs was often incomplete. Hemorrhagic complications were frequent, even when the specified intent was pre-embolization before surgery or SRS. Because the role of endovascular treatment remains uncertain, it should preferably, when possible, be offered in the context of a randomized trial.

OBJECTIVE The Treatment of Brain Arteriovenous Malformations Study (TOBAS) is a pragmatic study that includes 2 randomized trials and registries of treated or conservatively managed patients. The authors report the results of the surgical registry. METHODS TOBAS patients are managed according to an algorithm that combines clinical judgment and randomized allocation. For patients considered for curative treatment, clinicians selected from surgery, endovascular therapy, or radiation therapy as the primary curative method, and whether observation was a reasonable alternative. When surgery was selected and observation was deemed unreasonable, the patient was not included in the randomized controlled trial but placed in the surgical registry. The primary outcome of the trial was mRS score > 2 at 10 years (at last follow-up for the current report). Secondary outcomes include angiographic results, perioperative serious adverse events, and permanent treatment-related complications leading to mRS score > 2. RESULTS From June 2014 to May 2021, 1010 patients were recruited at 30 TOBAS centers. Surgery was selected for 229/512 patients (44%) considered for curative treatment; 77 (34%) were included in the surgery versus observation randomized trial and 152 (66%) were placed in the surgical registry. Surgical registry patients had 124/152 (82%) ruptured and 28/152 (18%) unruptured arteriovenous malformations (AVMs), with the majority categorized as low-grade Spetzler-Martin grade I–II AVM (118/152 [78%]). Thirteen patients were excluded, leaving 139 patients for analysis. Embolization was performed prior to surgery in 78/139 (56%) patients. Surgical angiographic cure was obtained in 123/139 all-grade (89%, 95% CI 82%–93%) and 105/110 low-grade (95%, 95% CI 90%–98%) AVM patients. At the mean follow-up of 18.1 months, 16 patients (12%, 95% CI 7%–18%) had reached the primary safety outcome of mRS score > 2, including 11/16 who had a baseline mRS score ≥ 3 due to previous AVM rupture. Serious adverse events occurred in 29 patients (21%, 95% CI 15%–28%). Permanent treatment-related complications leading to mRS score > 2 occurred in 6/139 patients (4%, 95% CI 2%–9%), 5 (83%) of whom had complications due to preoperative embolization. CONCLUSIONS The surgical treatment of brain AVMs in the TOBAS registry was curative in 88% of patients. The participation of more patients, surgeons, and centers in randomized trials is needed to definitively establish the role of surgery in the treatment of unruptured brain AVMs. Clinical trial registration no.: NCT02098252 (ClinicalTrials.gov)

Background: The prognosis for patients with recurrent glioblastoma (GBM) is dismal, and the question of repeat surgery at time of recurrence is common. Re-operation in the management of these patients remains controversial, as there is no randomized evidence of benefit. An all-inclusive pragmatic care trial is needed to evaluate the role of repeat resection. Methods: 3rGBM is a multicenter, pragmatic, prospective, parallel-group randomized care trial, with 1:1 allocation to repeat resection or standard care with no repeat resection. To test the hypothesis that repeat resection can improve overall survival by at least 3 months (from 6 to 9 months), 250 adult patients with prior resection of pathology-proven glioblastoma for whom the attending surgeon believes repeat resection may improve quality survival will be enrolled. A surrogate measure of quality of life, the number of days outside of hospital/nursing/palliative care facility, will also be compared. Centers are invited to participate without financial compensation and without contracts. Clinicians may apply to local authorities to approve an investigator-led in-house trial, using a common protocol, web-based randomization platform, and simple standardized case report forms. Discussion: The 3rGBM trial is a modern transparent care research framework with no additional risks, tests, or visits other than what patients would encounter in normal care. The burden of proof remains on repeat surgical management of recurrent GBM, because this management has yet to be shown beneficial. The trial is designed to help patients and surgeons manage the uncertainty regarding optimal care. Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT04838782.

BACKGROUND AND PURPOSE: Noninvasive angiography is commonly used to assess the outcome of surgical or endovascular treatment of intracranial aneurysms in clinical series or randomized trials. We sought to assess whether a standardized 3-grade classification system could be reliably used to compare the CTA and MRA results of both treatments. MATERIALS AND METHODS: An electronic portfolio composed of CTAs of 30 clipped and MRAs of 30 coiled aneurysms was independently evaluated by 24 raters of diverse experience and training backgrounds. Twenty raters performed a second evaluation 1 month later. Raters were asked which angiographic grade and management decision (retreatment; close or long-term follow-up) would be most appropriate for each case. Agreement was analyzed using the Krippendorff α (α(K)) statistic, and the relationship between angiographic grade and clinical management choice, using the Fisher exact and Cramer V tests. RESULTS: Interrater agreement was substantial (α(K) = 0.63; 95% CI, 0.55–0.70); results were slightly better for MRA results of coiling (α(K) = 0.69; 95% CI, 0.56–0.76) than for CTA results of clipping (α(K) = 0.58; 95% CI, 0.44–0.69). Intrarater agreement was substantial to almost perfect. Interrater agreement regarding clinical management was moderate for both clipped (α(K) = 0.49; 95% CI, 0.32–0.61) and coiled subgroups (α(K) = 0.47; 95% CI, 0.34–0.54). The choice of clinical management was strongly associated with the size of the residuum (mean Cramer V = 0.77 [SD, 0.14]), but complete occlusions (grade 1) were followed more closely after coiling than after clipping (P = .01). CONCLUSIONS: A standardized 3-grade scale was found to be a reliable and clinically meaningful tool to compare the results of clipping and coiling of aneurysms using CTA or MRA.

Background A significant proportion of glioblastoma (GBM) patients are considered for repeat resection, but evidence regarding best management remains elusive. Our aim was to measure the degree of clinical uncertainty regarding reoperation for patients with recurrent GBM. Methods We first performed a systematic review of agreement studies examining the question of repeat resection for recurrent GBM. An electronic portfolio of 37 pathologically confirmed recurrent GBM patients including pertinent magnetic resonance images and clinical information was assembled. To measure clinical uncertainty, 26 neurosurgeons from various countries, training backgrounds, and years' experience were asked to select best management (repeat surgery, other nonsurgical management, or conservative), confidence in recommended management, and whether they would include the patient in a randomized trial comparing surgery with nonsurgical options. Agreement was evaluated using κ statistics. Results The literature review did not reveal previous agreement studies examining the question. In our study, agreement regarding best management of recurrent GBM was slight, even when management options were dichotomized (repeat surgery vs. other options; κ=0.198 [95% confidence interval: 0.133-0.276]). Country of practice, years' experience, and training background did not change results. Disagreement and clinical uncertainty were more pronounced within clinicians with (κ=0.167 [0.055-0.314]) than clinicians without neuro-oncology fellowship training (κ=0.601 [0.556-0.646]). A majority (51%) of responders were willing to include the patient in a randomized trial comparing repeat surgery with nonsurgical alternatives in 26/37 (69%) of cases. Conclusion There is sufficient uncertainty and equipoise regarding the question of reoperation for patients with recurrent glioblastoma to support the need for a randomized controlled trial.

Results of surgical or endovascular treatment of intracranial aneurysms are often assessed using angiography. A reliable method to report results irrespective of treatment modality is needed to enable comparisons. Our goals were to systematically review existing classification systems, and to propose a 3-point classification applicable to both treatments and assess its reliability. We conducted two systematic reviews on classification systems of angiographic results after clipping or coiling to select a simple 3-category scale that could apply to both treatments. We then circulated an electronic portfolio of angiograms of clipped (n=30) or coiled (n=30) aneurysms, and asked raters to evaluate the degree of occlusion using this scale. Raters were also asked to choose an appropriate follow-up management for each patient based on the degree of occlusion. Agreement was assessed using Krippendorff’s α statistics (αK), and relationship between occlusion grade and clinical management was analyzed using Fisher’s exact and Cramer’s V tests. The systematic reviews found 70 different grading scales with heterogeneous reliability (kappa values from 0.12 to 1.00). The 60-patient portfolio was independently evaluated by 19 raters of diverse backgrounds (neurosurgery, radiology, and neurology) and experience. There was substantial agreement (αK=0.76, 95%CI, 0.67–0.83) between raters, regardless of background, experience, or treatment used. Intra-rater agreement ranged from moderate to almost perfect. A strong relationship was found between angiographic grades and management decisions (Cramer’s V: 0.80±0.12). A simple 3-point scale demonstrated sufficient reliability to be used in reporting aneurysm treatments or in evaluating treatment results in comparative randomized trials.

BACKGROUND AND PURPOSE: Conventional angiography is the benchmark examination to diagnose cerebral vasospasm, but there is limited evidence regarding its reliability. Our goals were the following: 1) to systematically review the literature on the reliability of the diagnosis of cerebral vasospasm using conventional angiography, and 2) to perform an agreement study among clinicians who perform endovascular treatment. MATERIALS AND METHODS: Articles reporting a classification system on the degree of cerebral vasospasm on conventional angiography were systematically searched, and agreement studies were identified. We assembled a portfolio of 221 cases of patients with subarachnoid hemorrhage and asked 17 raters with different backgrounds (radiology, neurosurgery, or neurology) and experience (junior ≤10 and senior >10 years) to independently evaluate cerebral vasospasm in 7 vessel segments using a 3-point scale and to evaluate, for each case, whether findings would justify endovascular treatment. Nine raters took part in the intraobserver reliability study. RESULTS: The systematic review showed a very heterogeneous literature, with 140 studies using 60 different nomenclatures and 21 different thresholds to define cerebral vasospasm, and 5 interobserver studies reporting a wide range of reliability (κ = 0.14–0.87). In our study, only senior raters reached substantial agreement (κ ≥ 0.6) on vasospasm of the supraclinoid ICA, M1, and basilar segments and only when assessments were dichotomized (presence or absence of ≥50% narrowing). Agreement on whether to proceed with endovascular management of vasospasm was only fair (κ ≤ 0.4). CONCLUSIONS: Research on cerebral vasospasm would benefit from standardization of definitions and thresholds. Dichotomized decisions by experienced readers are required for the reliable angiographic diagnosis of cerebral vasospasm.

BACKGROUND AND PURPOSE: After aneurysmal SAH, transcranial Doppler is commonly used to monitor cerebral vasospasm. The diagnostic accuracy of transcranial Doppler flow velocity values in detecting angiographic vasospasm in patients requiring urgent endovascular intervention has not been established. MATERIALS AND METHODS: We performed a retrospective analysis of a consecutive series of patients with aneurysmal SAH who underwent transcranial Doppler (index test) within 24 hours of conventional angiography (reference test). The judgment of 33%, 50%, and 66% degree of vessel narrowing on angiography was independently established by multiple neuroendovascular clinicians. Vessel-specific per-segment and per-patient transcranial Doppler velocities were studied using receiver operating characteristic curves, the Youden index, and minimal acceptable sensitivity models. Optimal mean flow-velocity thresholds were explored to calculate sensitivity and specificity using a per-patient judgment of vasospasm of at least 50% angiographic narrowing in any large arterial segment except A1. RESULTS: In 221 patients, vasospasm was found in 15%, 8%, and 4% of arteries when the degree of reference angiographic luminal narrowing was 33%, 50%, and 66%, respectively. Mean flow velocities were significantly higher in vasospastic segments (P = . 001), but per-segment exploratory analyses yielded unsound mean flow velocity thresholds. The Youden and minimal acceptable sensitivity models proposed mean flow velocity thresholds of approximately 160 cm/s for the anterior circulation and 80 cm/s for the posterior circulation in the per-patient diagnosis of angiographic vasospasm (≥50%), yielding a sensitivity of 80%–90% (95% CI, 0.77–0.96), but with a corresponding specificity of 50% (95% CI, 0.40–0.56). CONCLUSIONS: In this study, a threshold transcranial Doppler mean flow-velocity value that would accurately diagnose ≥50% angiographic vasospasm remained elusive.

Background and purpose Appropriate management of ruptured intracranial aneurysm (RIA) in patients eligible for surgical clipping but under-represented in or excluded from previous randomized trials remains undetermined. Methods The International Subarachnoid Aneurysm Trial-2 (ISAT-2) is a randomized care trial comparing surgical versus endovascular treatment (EVT) of RIA. All patients considered for surgical clipping but eligible for endovascular treatment can be included. The primary endpoint is death or dependency on modified Rankin score (mRS > 2) at 1 year. Secondary endpoints are 1 year angiographic results and length of hospital stay. Results An interim analysis was performed after 103 patients were treated from November 2012 to July 2017 in 4 active centers. Fifty-two of the 55 patients allocated to surgery were treated by clipping, and 45 of the 48 allocated to EVT were treated by coiling, with 3 crossovers in each arm. The main endpoint (1 year mRS > 2), available for 76 patients, was reached in 16/42 patients allocated to clipping (38%; 95%CI: 25%–53%), and 10/34 patients allocated to coiling (29%; 17%–46%). One year imaging results were available in 54 patients: complete aneurysm occlusion was found in 23/27 patients allocated to clipping (85%; 67%–94%), and 18/27 patients allocated to coiling (67%; 47%–81%). Hospital stay exceeding 20 days was more frequent in surgery (26/55 [47%; 34%–60%]) than EVT (9/48 [19%; 10%–31%]). Conclusion Ruptured aneurysm patients for whom surgical clipping may still be best can be managed in a randomized care trial, which is feasible in some centers. More participating centers are needed.

OBJECTIVEThe Medina embolization device (MED) is a novel, braided self-expanding endovascular device designed to occlude aneurysms by constructing an in situ intrasaccular flow diverter. Although a single device can be positioned at the neck of simple spherical in vitro aneurysms, the best way to occlude more complex in vivo aneurysms (using multiple MEDs or a combination of MEDs and platinum coils) is currently unknown.METHODSFifty-two aneurysms of 3 different types were created in 31 canines, yielding 48 patent aneurysms. Treatments were randomly allocated by drawing lots: group 1, MEDs alone (n = 16); group 2, MEDs plus standard platinum coils (n = 16); and group 3, control aneurysms treated with coils alone (n = 16). Angiographic results were scored and compared immediately following treatment completion and at 3 months. Specimens were photographed and the extent of neointimal closure of the aneurysmal neck scored, followed by histopathological analyses.RESULTSAngiographic scores of 0 or 1 (occlusion or near occlusion) were initially obtained in 2 of 16 (12.5%, 95% CI 1.6%–38.3%) group 1 (MEDs alone), 3 of 16 (18.7%, 95% CI 4%–45.6%) group 2 (MEDs plus coils), and 10 of 16 (62.5%, 95% CI 35.4%–84.8%) group 3 (coils alone) aneurysms (p = 0.005). At 3 months, scores of 0 or 1 were found in 11 of 16 (68.7%, 95% CI 41.3%–89.0%) group 1, 9 of 16 (56.2%, 95% CI 29.9%–80.2%) group 2, and 8 of 16 (50%, 95% CI 24.7%–75.3%) group 3 aneurysms (p = 0.82). Neointimal scores were similar for the 3 treated groups (p = 0.66).CONCLUSIONEndovascular treatment of experimental aneurysms with MEDs or MEDs and coils showed angiographic occlusion and neointimal scores at 3 months that were similar to those achieved with standard platinum coiling.

Whether the best management of middle cerebral artery (MCA) aneurysm patients is surgical or endovascular remains uncertain, with little evidence to guide decision-making. A randomized care trial offering MCA aneurysm patients a 50% chance of surgical and a 50% chance of endovascular management may optimize outcomes in the presence of uncertainty.The Middle Cerebral Artery Aneurysm Trial (MCAAT) is an investigator-initiated, multicenter, parallel group, prospective, 1:1 randomized controlled clinical trial. All adult patients with MCA aneurysms, ruptured or unruptured, amenable to surgical and endovascular treatment can be included. The composite primary outcome is "Treatment Success": (i) occlusion or exclusion of the aneurysm using the allocated treatment modality; (ii) no intracranial hemorrhage during follow-up; (iii) no retreatment of the target aneurysm during follow-up, (iv) no residual aneurysm on angiographic follow-up; and (v) independence (mRS3) at 1 year. The trial tests 2 versions of the same hypothesis (one for ruptured and one for unruptured MCA aneurysm patients): Surgical management will lead to a 15% absolute increase in the proportion of patients reaching Treatment Success from 55% to 70% (ruptured) or from 75% to 90% (unruptured aneurysm patients) compared with endovascular treatment (any method). In this pragmatic trial, outcome evaluations are by treating physicians, except for 1-year angiographic results which will be core lab assessed. The trial will be monitored by an independent data safety monitoring committee to assure safety of participants. MCAAT is registered at clinicaltrials.gov: NCT05161377.Patients with MCA aneurysms can be optimally managed within a care trial protocol.

Objective There are few randomized data comparing clipping and coiling for middle cerebral artery (MCA) aneurysms. We analyzed results from patients with MCA aneurysms enrolled in the CURES (Collaborative UnRuptured Endovascular vs. Surgery) and ISAT-2 (International Subarachnoid Aneurysm Trial II) randomized trials. Methods Both trials are investigator-led parallel-group 1:1 randomized studies. CURES includes patients with 3-mm to 25-mm unruptured intracranial aneurysms (UIAs), and ISAT-2 includes patients with ruptured aneurysms (RA) for whom uncertainty remains after ISAT. The primary outcome measure of CURES is treatment failure: 1) failure to treat the aneurysm, 2) intracranial hemorrhage during follow-up, or 3) residual aneurysm at 1 year. The primary outcome of ISAT-2 is death or dependency (modified Rankin Scale score >2) at 1 year. One-year angiographic outcomes are systematically recorded. Results There were 100 unruptured and 71 ruptured MCA aneurysms. In CURES, 90 patients with UIA have been treated and 10 await treatment. Surgical and endovascular management of unruptured MCA aneurysms led to treatment failure in 3/42 (7%; 95% confidence interval [CI], 0.02–0.19) for clipping and 13/48 (27%; 95% CI, 0.17–0.41) for coiling (P = 0.025). All 71 patients with RA have been treated. In ISAT-2, patients with ruptured MCA aneurysms managed surgically had died or were dependent (modified Rankin Scale score >2) in 7/38 (18%; 95% CI, 0.09–0.33) cases, and 8/33 (24%; 95% CI, 0.13–0.41) for endovascular. One-year imaging results were available in 80 patients with UIA and 62 with RA. Complete aneurysm occlusion was found in 30/40 (75%; 95% CI, 0.60–0.86) patients with UIA allocated clipping, and 14/40 (35%; 95% CI, 0.22–0.50) patients with UIA allocated coiling. Complete aneurysm occlusion was found in 24/34 (71%; 95% CI, 0.54–0.83) patients with RA allocated clipping, and 15/28 (54%; 95% CI, 0.36–0.70) patients with RA allocated coiling. Conclusions Randomized data from 2 trials show that better efficacy may be obtained with surgical management of patients with MCA aneurysms.

Background The pressure cooker (PC) technique uses a second microcatheter to produce a proximal occlusion to prevent the reflux of liquid embolic agent (LEA) injected through a more distal microcatheter, and can be used to treat arteriovenous malformations and dural arteriovenous fistulae. The liquid embolic Magic Glue (MG) (N-hexyl cyanoacrylate (NHCA)) has been introduced as an alternative to N-butyl cyanoacrylate (NBCA). Our goals were to compare the extent of embolization of rete mirabile with or without the PC technique using NBCA or MG, and to compare the proximal occlusions obtained with MG or NBCA while using the PC technique in a renal arterial model. Methods Rete mirabile were embolized with (n = 4) and without (n = 4) the PC technique, using MG (n = 4) or NBCA (n = 4). A renal arterial model was then used to study the characteristics of the MG plug (n = 10) used for the PC technique, and resistance to catheter withdrawal as compared to NBCA (n = 4). Specimens were analyzed macro- and microscopically and compared to angiographic results. Results Extent of rete embolization with CYA agents was not significantly greater when using the PC technique. Results were similar with both types of cyanoacrylate (p = 0.657). The force necessary to withdraw the microcatheter was less with MG than with NBCA (p = 0.035). Conclusion MG was similar to NBCA in extent of rete embolization. Less traction force was necessary to withdraw trapped non-detachable microcatheters using MG compared to NBCA.

In the absence of randomized evidence, the optimal management of patients with unruptured intracranial aneurysms (UIA) remains uncertain.Comprehensive Aneurysm Management (CAM) is an all-inclusive care trial combined with a registry. Any patient with a UIA (no history of intracranial hemorrhage within the previous 30 days) can be recruited, and treatment allocation will follow an algorithm combining clinical judgment and randomization. Patients eligible for at least 2 management options will be randomly allocated 1:1 to conservative or curative treatment. Minimization will be used to balance risk factors, using aneurysm size (≥7 mm), location (anterior or posterior circulation), and age60 years.The CAM primary outcome is survival without neurologic dependency (modified Rankin Scale [mRS] score3) at 10 years. Secondary outcome measures include the incidence of subarachnoid hemorrhage during follow-up and related morbidity and mortality; morbidity and mortality related to endovascular treatment or surgical treatment of the UIA at 1 year; overall morbidity and mortality at 1, 5, and 10 years; when relevant, duration of hospitalization; and, when relevant, discharge to a location other than home. The primary hypothesis for patients randomly allocated to at least 2 options, 1 of which is conservative management, is that active UIA treatment will reduce the 10-year combined neurologic morbidity and mortality (mRS score2) from 24% to 16%. At least 961 patients recruited from at least 20 centers over 4 years will be needed for the randomized portion of the study.Patients with unruptured intracranial aneurysms can be comprehensively managed within the context of an all-inclusive care trial.

Flow diversion is increasingly used for treating intracranial aneurysms. This article aims to review the evidence obtained from animal models and summarizes the findings that might be of clinical interest. From a systematic review of studies published between 2000 and 2016, we extracted the data on the following questions: What roles do aneurysm dimension, morphology, and vascular geometry have on success of flow diversion? What characteristics of a flow diverter can influence aneurysm occlusion? What are the risk factors for jailed branch occlusion? Flow diversion has been shown to be less effective in occluding large aneurysms with wide or undefined necks, as compared to smaller aneurysms with narrower necks. Straight sidewall aneurysms were more likely to occlude after flow diversion than curved sidewall aneurysms or bifurcation aneurysms with branches originating from the neck or the fundus. The main characteristics of devices that may impact on the success of flow diversion are porosity and pore-density, but challenging aneurysm models were not better occluded with devices of lower porosity. Porosity is not uniform when devices deform to adapt to local in vivo anatomy when deployed. Neointima formation on devices correlates with low porosity. Branches are rarely occluded when they are jailed, but persistent branch flow may prevent aneurysm occlusion. Experimental models may help anticipate clinical results of flow diversion.

BackgroundFlow diverters (FDs) are increasingly used for bifurcation aneurysms. Failure of aneurysm occlusion may be caused by residual flow maintaining patency of the jailed branch along with the aneurysm. Our aim was to test whether endovascular occlusion of the jailed branch could improve efficacy of flow diversion of bifurcation aneurysms.Materials and methodsSixteen wide-necked lingual–carotid artery bifurcation aneurysms were created in eight canines. Patent aneurysms were randomly allocated 4 weeks later to flow diversion combined with jailed branch occlusion using coils and/or Onyx (n=6) or flow diversion alone (n=8). Angiographic results of aneurysm occlusion at 3 months were scored using an ordinal scale. Pathology specimens were photographed and neointimal coverage estimated using a semiquantitative scoring system.ResultsFourteen aneurysms were patent at 1 month. FD deployment was successful in all cases but, at 3-month follow-up, three devices had prolapsed into the aneurysm. None of the bifurcation aneurysms treated with FD alone were occluded at 3 months. Endovascular branch occlusion combined with flow diversion significantly improved aneurysm occlusion rates compared with flow diversion alone (median angiographic scores 2 vs 0: p=0.0137). Flow-limiting parent vessel stenosis was not observed in any arteries. Devices were covered with thick neointima in most cases, but patent aneurysms were associated with leaks or holes in the neointima covering the aneurysm neck.ConclusionsTreatment failures following flow diversion of bifurcation aneurysms can be caused by persistent flow to the jailed branch. Branch occlusion combined with flow diversion may improve angiographic occlusion scores of a canine bifurcation aneurysm model.

Flow diversion (FD) is increasingly used to treat intracranial aneurysms. We sought to systematically review published studies to assess the quality of reporting and summarize the results of FD in various animal models. Databases were searched to retrieve all animal studies on FD from 2000 to 2015. Extracted data included species and aneurysm models, aneurysm and neck dimensions, type of flow diverter, occlusion rates, and complications. Articles were evaluated using a checklist derived from the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines. Forty-two articles reporting the results of FD in nine different aneurysm models were included. The rabbit elastase-induced aneurysm model was the most commonly used, with 3-month occlusion rates of 73.5 %, (95 %CI [61.9–82.6 %]). FD of surgical sidewall aneurysms, constructed in rabbits or canines, resulted in high occlusion rates (100 % [65.5–100 %]). FD resulted in modest occlusion rates (15.4 % [8.9–25.1 %]) when tested in six complex canine aneurysm models designed to reproduce more difficult clinical contexts (large necks, bifurcation, or fusiform aneurysms). Adverse events, including branch occlusion, were rarely reported. There were no hemorrhagic complications. Articles complied with 20.8 ± 3.9 of 41 ARRIVE items; only a small number used randomization (3/42 articles [7.1 %]) or a control group (13/42 articles [30.9 %]). Preclinical studies on FD have shown various results. Occlusion of elastase-induced aneurysms was common after FD. The model is not challenging but standardized in many laboratories. Failures of FD can be reproduced in less standardized but more challenging surgical canine constructions. The quality of reporting could be improved.

BACKGROUND AND PURPOSE: Liquid embolic agents are increasingly used to treat vascular malformations. We sought to assess embolization with these agents by using a dual-lumen balloon catheter in an experimental setting. MATERIALS AND METHODS: Eighteen injections of liquid embolic agents were performed in the rete mirabile of swine. We used 3 methods to control liquid embolic agent reflux: 1) dual-lumen balloon-catheter (group A, n = 8); 2) injection of liquid embolic agent after proximal n-BCA plug formation through a second microcatheter (group B, n = 4); and 3) standard liquid embolic agent injection (group C, controls, n = 6). The following outcomes were graded by using ordinal scales by angiography, macrophotography, and radiography of retia after euthanasia: 1) angiographic and pathologic extent of liquid embolic agent embolization of the rete, 2) reflux of liquid embolic agents in the parent artery, and 3) density of liquid embolic agents in the proximal rete. Technical complications were also recorded. A successful injection was defined as an embolization that reached the contralateral rete without reflux into proximal external branches. Exact logistic regression analyses were performed to compare groups. RESULTS: There were significant differences among groups for reflux (P = .029) and liquid embolic agent density in the proximal rete (P = .014), while extension to the contralateral rete did not reach statistical significance (P = .07). Injections differed among groups (P = .004), with dual-lumen balloon-catheter injections more frequently successful compared with control injections (P = .019). CONCLUSIONS: Dual-lumen balloon catheters allowed better liquid embolic agent injections than standard injections.

Objective Flow diverters (FDs) are increasingly used to treat difficult intracranial aneurysms. The objective of this study was to test whether treatment challenges posed by giant curved sidewall (cSW) and endwall bifurcation (EwB) aneurysms can be overcome with the use of very-low-porosity devices. Methods Large and giant EwB (n = 12) and cSW aneurysms (n = 5) were constructed in 17 dogs. EwB aneurysms were treated with 48 (n = 4), 64 (n = 4), or two overlapping 64-wire low-porosity devices (n = 4), whereas all cSW aneurysms were treated with single 64-wire devices. Angiographic results were recorded immediately and at 12 weeks before euthanasia. Pathologic specimens were photographed and neointimal coverage of devices measured and scored. Results By 12 weeks, 1 of 12 EwB and 1 of 5 cSW aneurysms were occluded. All other aneurysms were patent. Device-related arterial stenoses occurred in 13 of 17 animals, hemodynamically significant in two. All branches jailed by the FDs remained patent. There was a significant correlation between angiographic scores and the degree of neointima formation on the device (Rho = 0.527; P = 0.04). Failures of aneurysm occlusion could be explained by holes, sometimes barely visible, in the neointima that formed over FDs. Conclusion Low-porosity FDs fail to reliably occlude experimental giant EwB and cSW aneurysms.

OBJECTIVERuptured intracranial aneurysms (RIAs) can be managed surgically or endovascularly. In this study, the authors aimed to measure the interobserver agreement in selecting the best management option for various patients with an RIA.METHODSThe authors constructed an electronic portfolio of 42 cases of RIA in which an angiographic image along with a brief clinical vignette for each patient were displayed. Undisclosed to the responders was that the RIAs had been categorized as International Subarachnoid Aneurysm Trial (ISAT) (small, anterior-circulation, non–middle cerebral artery location, n = 18) and non-ISAT (n = 22) aneurysms; the non-ISAT group also included 2 basilar apex aneurysms for which a high number of endovascular choices was expected. The portfolio was sent to 132 clinicians who manage patients with RIAs and circulated to members of an American surgical association. Judges were asked to choose between surgical and endovascular management, to indicate their level of confidence in the choice of treatment on a quantitative 0–10 scale, and to determine whether they would include the patient in a randomized trial in which both treatments are compared. Eleven clinicians were asked to respond twice at least 1 month apart. Responses were analyzed using kappa statistics.RESULTSEighty-five clinicians (58 cerebrovascular surgeons, 21 interventional neuroradiologists, and 6 interventional neurologists) answered the questionnaire. Overall, endovascular management was chosen more frequently (n = 2136 [59.8%] of 3570 answers). The proportions of decisions to clip were significantly higher for non-ISAT (50.8%) than for ISAT (26.2%) aneurysms (p = 0.0003). Interjudge agreement was only fair (kappa 0.210, 95% CI 0.158–0.276) for all cases and judges, despite high confidence levels (mean score > 8 for all cases). Agreement was no better within subgroups of clinicians with the same specialty, years of experience, or location of practice or across capability groups (ability to clip or coil, or both). When agreement was defined as > 80% of responders choosing the same option, agreement occurred for only 7 of 40 cases, all of which were ISAT aneurysms, for which coiling was preferred.CONCLUSIONSAgreement between clinicians regarding the best management option was infrequent but centered around coiling for some ISAT aneurysms. Surgical clipping was chosen more frequently for non-ISAT aneurysms than for ISAT aneurysms. Patients with such an aneurysm might be candidates for inclusion in randomized trials.

Background Unruptured intracranial aneurysms (UIAs) are increasingly diagnosed and are commonly treated using endovascular treatment or microsurgical clipping. The safety and efficacy of treatments have not been compared in a randomised trial. How to treat patients with UIAs suitable for both options remains unknown. Methods We randomly allocated clipping or coiling to patients with one or more 3–25 mm UIAs judged treatable both ways. The primary outcome was treatment failure, defined as: initial failure of aneurysm treatment, intracranial haemorrhage or residual aneurysm on 1-year imaging. Secondary outcomes included neurological deficits following treatment, hospitalisation >5 days, overall morbidity and mortality and angiographic results at 1 year. Results The trial was designed to include 260 patients. An analysis was performed for slow accrual: 136 patients were enrolled from 2010 through 2016 and 134 patients were treated. The 1-year primary outcome, available for 104 patients, was reached in 5/48 (10.4% (4.5%–22.2%)) patients allocated surgical clipping, and 10/56 (17.9% (10.0%–29.8%)) patients allocated endovascular coiling (OR: 0.54 (0.13–1.90), p=0.40). Morbidity and mortality (modified Rankin Scale>2) at 1 year occurred in 2/48 (4.2% (1.2%–14.0%)) and 2/56 (3.6% (1.0%–12.1%)) patients allocated clipping and coiling, respectively. New neurological deficits (15/65 vs 6/69; OR: 3.12 (1.05–10.57), p=0.031), and hospitalisations beyond 5 days (30/65 vs 6/69; OR: 8.85 (3.22–28.59), p=0.0001) were more frequent after clipping. Conclusion Surgical clipping or endovascular coiling of UIAs did not show differences in morbidity at 1 year. Trial continuation and additional randomised evidence will be necessary to establish the supposed superior efficacy of clipping.

Introduction et objectifs La « Pressure Cooker technique (PC) » est une technique endovasculaire avec 2 microcatheters qui reduit le reflux des agents emboliques au moyen d’un bouchon proximal. En utilisant un modele porcin et plusieurs cyanoacrylates, nous avons effectue une technique PC et une injection reguliere sans bouchon proximal afin de comparer la penetration des agents emboliques liquides dans le rete mirabile. Nous avons evalue egalement, en injectant dans les arteres des reins a l’aide de PC, la force necessaire pour retirer les microcatethers a la fin de la injection. Materiaux et methodes Huit porcs ont ete utilises pour les injections dans la Rete mirabile. Nous avons utilise les cyanoacrylates et PC technique en 4 injections et une injection conventionnelle dans 4 autres (groupe temoin). Nous avons utilise deux types de cyanoacrylates, le NBCA et un cyanoacrylate non adhesif (n = 4), l’alpha-hexil-cyanoacrylate (Magic Glue MG, n = 4). La penetration dans le rete a ete evaluee par radiographie a l’aide d’echelles ordinales apres euthanasie. Dans les arteres renales segmentaires, 14 injections utilisant PC ont ete realisees utilisant MG pour le plug (n = 10) et utilisant NBCA pour le plug (n = 4). La force necessaire pour retirer les microcatheters a ete evaluee avec une echelle numerique. Resultats Aucune difference significative n’a ete trouvee pour la penetration du cyanoacrylate dans le Rete Mirabile pour les groupes PC et non-PC (p = 0,657) et concernant la penetration entre MG et NBCA (p = 0,657). En ce qui concerne les forces necessaires pour retirer le catheter distal, elles etaient moins importantes lorsque MG etait utilise proximalement que NBCA (p = 0,035). La variation de longueur du bouchon proximal etait significative avec MG (p = 0,005) mais non avec NBCA (p = 0,066). Aucune difference n’a ete trouvee concernant les mouvements des bobines (p = 0,517) Conclusions La PC technique utilisant un bouchon proximal et des injections distales de cyanoacrylates n’a pas ameliore l’embolisation du Rete Mirabile dans cette etude. L’utilisation d’alpha-hexil-cyanoacrylate (MG) peut reduire les forces de traction lors du retrait du microcatheter, mais la longueur du bouchon proximal initial a tendance a augmenter.

OBJECTIVE Surgical management of recurrent aneurysms following failed flow diversion may pose difficulties in securing vascular control with temporary clips. The authors tested the efficacy and impact of different types of aneurysm clips on flow-diverted arteries. METHODS Six wide-necked experimental aneurysms were created in canines and treated with Pipeline flow diverters. In 4 aneurysms, occlusion of the artery at the level of the proximal and distal landing zones (n = 2 per aneurysm) was attempted, using temporary, fenestrated, single, and double permanent aneurysm clips. Two aneurysms served as unclipped controls. Serial angiography was performed to investigate the efficacy of clip occlusion, flow diverter deformation, and thrombus formation. After the animals were killed, the flow-diverted aneurysm constructs were opened and photographed to determine neointimal or device damage as a result of clip placement. RESULTS Angiography-confirmed clip occlusion was only possible for 4 of 8 of the tested flow-diverted arterial segments. Clip application attempts led to filling defects consistent with thrombus formation in 2 of 4 flow-diverted constructs, and to minor damage of the flow diverter with neointimal fracture in 1 of 4 cases. CONCLUSIONS Aneurysm clips placed on canine parent arteries bearing a Pipeline flow diverter were unable to reliably stop blood flow. Application of aneurysm clips can cause mild damage to the device and neointima, which might translate into thromboembolic risks. If possible, vascular control should be sought beyond the terminal ends of the implanted device.

Purpose Flow diverters (FDs) have led to spectacular results in otherwise untreatable aneurysm cases, but complications can occur. There is a pressing need to study factors that might predict their safety and efficacy. Methods The anatomical constraints that may impact on the ability of FDs to redirect blood flow and provide a scaffold for neointima formation across the aneurysm or branch ostia are explored and classified. A nomenclature is needed to identify the key factors that should be taken into account before contemplating the use of FDs in clinical aneurysms, and that should be reproduced in experimental models, if they are to guide safe clinical use. Results The free stent segment (FSS), the portion of the device that covers an aneurysm or branch origin, dictates whether aneurysms or branches will remain patent. Three levels of increasing complexity must be taken into account to anticipate what will occur at the FSS level. (1) Virtual models can provide basic principles; (2) in vitro studies allow testing FSS deformations that may occur in various anatomical circumstances and impact on efficacy and safety; (3) but only in vivo studies can provide key information on neointimal closure following implantation that will differentiate success from failure. Conclusions A nomenclature is necessary to determine the optimal or suboptimal conditions for FDs and to design the virtual, in vitro and in vivo studies that will allow a better understanding of the factors involved in the success or failure of this novel treatment.

Object Flow diverters (FDs) are increasingly used to treat complex intracranial aneurysms, but preclinical studies that could guide clinical applications are lacking. The authors designed a modular aneurysm model in canines to address this problem. Methods Three variants of one modular aneurysm model were constructed in 21 animals. Sidewall (n = 5), curved sidewall (n = 5), and end-wall bifurcation (n = 7) aneurysms were treated with prototype 36-wire FDs. Four more end-wall bifurcation aneurysms were treated with prototype 48-wire lower-porosity FDs. Angiographic results postimplantation and at 3 months were scored with an ordinal scale. Animals were euthanized at 3 (n = 17) or 6 (n = 3) months, and the FD covering the aneurysm ostium was photographed to analyze metallic porosity and amount of neointima formation. Results Straight sidewall aneurysms were better occluded than curved sidewall and end-wall bifurcation aneurysms at the 3-month angiography follow-up (p = 0.010). Flow diverters failed to occlude curved sidewall aneurysms (n = 0/5) and all but one (n = 1/7) end-wall bifurcation aneurysm. Angiographic results were no better (n = 0/4) using a 48-wire FD (p = 0.788). Branches jailed by the FD (n = 16) remained patent in all cases. Metallic porosity was decreased (p = 0.014) and neointimal closure of the aneurysm ostium was more complete (p = 0.040) in sidewall aneurysms than in curved or bifurcation variants of the model. Conclusions Flow diverters may succeed in treating straight sidewall aneurysms, but the same device repeatedly fails to occlude curved sidewall and end-wall bifurcation aneurysms. In vivo studies can be designed to test basic principles that, once validated, may serve to guide clinical use of new devices.

BACKGROUND AND PURPOSE: FDs are new intracranial stents designed to occlude aneurysms while preserving flow to jailed arterial branches. We tested this fundamental principle in a new aneurysm model. MATERIALS AND METHODS: Canine lateral wall aneurysms, featuring a branch located immediately opposite the aneurysm, were created in 16 animals to study the effects on aneurysm or branch occlusion using single HP stents ( n = 4), 2 overlapping HP stents ( n = 4), or an FD ( n = 8). Two other animals, in which an efferent arterial branch was anastomosed to the aneurysm fundus, were also treated with FDs. Angiographic results after deployment, at 2 weeks, and at 3 months were scored using an ordinal scale. The metal porosity of the FSS and the amount of FSS neointima formation was determined by postmortem photography. RESULTS: FDs led to better angiographic occlusion scores compared with HP stents ( P = .026). FDs were significantly more likely to occlude the aneurysm than the branch ( P = .01). When the branch was switched to originate from the aneurysm fundus, the FDs became ineffective (0/2). Neointimal closure of the aneurysm ostium was significantly better with FDs than with single or double HP stents ( P = .039). Angiographic occlusion correlated with metallic porosity and neointimal tissue coverage (Spearman ρ = −0.81; P = .001). CONCLUSIONS: In this study, flow diverters occluded lateral wall aneurysms more readily than branches. Metal device porosity strongly influenced the occlusion rate. ASA : aspirin CCA : common carotid artery CFD : computational fluid dynamics FD : flow diverters FSS : free segment of stent HP : high- porosity

BACKGROUND AND PURPOSE: Angiographic results are commonly used as a surrogate marker of success of coiling of intracranial aneurysms. Inter- and intraobserver agreement in judging angiographic results remain poorly characterized. Our goal was to offer such an evaluation of a grading scale commonly used to evaluate results of endovascular treatment of aneurysms. MATERIALS AND METHODS: A portfolio of 90 angiographic images from 45 patients selected from the core lab data base of a randomized trial was sent to 12 observers on 2 occasions more than 3 months apart. The variability of a 3-value grading scale used to score angiographic results and of a final judgment regarding the presence of a recurrence was studied using κ statistics. RESULTS: Ten participants responded once and 6 responded twice. Agreement was poor to moderate (κ = 0.28–0.5) for senior and junior observers judging angiographic results immediately or 12–18 months after treatment. Agreement reached a reassuring “substantial” (κ = 0.62) level, with a dichotomous presence-absence of a major recurrence, and intraobserver agreement was better in experienced core lab assessors. CONCLUSIONS: There is an important variability in the assessment of angiographic outcomes of endovascular treatments, rendering comparisons between publications risky, if not invalid. A simple dichotomous judgment can be used as a surrogate outcome in randomized trials designed to assess the value of new endovascular devices.

BACKGROUND AND PURPOSE: Endovascular treatment of aneurysms may result in complete or incomplete occlusions or may be followed by recurrences. The goal of the present study was to better define pathologic features associated with so-called healing or recurrences after coiling and to propose an alternative concept to the currently accepted view. MATERIALS AND METHODS: Experimental canine venous pouch aneurysms were created by using a T-type (group A, N = 29) or a Y-type constructed bifurcation (group B, N = 37) between the carotid arteries. Coil embolization was performed 2 weeks later; and angiography, immediately after and at 12 weeks. Angiographic results, neointima formation at the neck, endothelialization, and organization of thrombus were compared between groups by using qualitative scores and immunohistochemistry. RESULTS: Angiographic results at 3 months were significantly better in group A than in group B ( P = .001). Macroscopic neointimal scores were also better ( P = .012). Only 10/32 aneurysms with satisfactory results at angiography were completely sealed by neointima formation. Animals with residual or recurrent aneurysms had significantly worse neointimal scores than those with completely occluded ones ( P = .0003). On histologic sections, the neointima was constantly present in “healed” and in recurrent aneurysms. This neointima was a multicellular layer of α-actin+ cells in a collagenous matrix, covered with a single layer of nitric oxide synthetase (NOS+) endothelial cells, whether it completely occluded the neck of the aneurysm or dived into the recurring or residual space between the aneurysm wall and the coil mass embedded in organizing thrombus. CONCLUSION: Complete angiographic occlusions at 3 months can be associated with incomplete neointimal closure of the neck at pathology. Thrombus organization, endothelialization, and neointima formation can occur concurrently with recurrences.

Despite the increasing use of embolic protection systems (EPS) for carotid stenting, their intrinsic in vivo thrombogenicity remains unknown. We studied three different types of EPS (n = 24) deployed in the carotid arteries of pigs in which pools of platelets and fibrinogen were labelled with 111In and 125I. The amount of clot deposition seen on photography was also scored using a qualitative scale. EPS made of fabric nets under normal flow conditions were 5–6 and 15–16 times more thrombogenic (for both platelet (P=.04) and fibrin (P=.007)) than Nitinol mesh nets. Clot deposition on Nitinol mesh nets was more abundant under flow arrest than under normal flow conditions (P=.018). EPS differ in intrinsic thrombogenicity, a characteristic of the material that could be investigated in pre-clinical studies designed to optimize devices.

BACKGROUND AND PURPOSE: The role of flow diversion in the management of aneurysms remains unknown. We sought to evaluate the community agreement regarding indications for flow diversion. MATERIALS AND METHODS: A portfolio of 35 difficult aneurysm cases was sent to 40 clinicians with varying backgrounds and experience. Responders were asked whether they considered flow diversion a treatment option, whether other options were possible, whether recruitment in a randomized trial would be considered, and to select their final choice. Agreement was studied by using κ statistics. RESULTS: Decisions for flow diversion were more frequent (n = 300, 39%) than decisions to coil (n = 163, 21.2%), to observe (n = 121, 15.7%), to occlude the parent vessel (n = 102, 13.2%), or to clip (n = 66, 8.6%). Sidewall aneurysm morphology was associated with flow diversion as the final choice (P = .001). Interjudge agreement was fair at best (κ

PURPOSE Endovascular embolization with platinum coils is sometimes followed by recanalization. The present study was undertaken to assess whether cryoablation of the endothelial lining could prevent recanalization after coil occlusion. MATERIALS AND METHODS Recanalization rates of canine maxillary and vertebral arteries ( n = 20) occluded with platinum coils with or without previous cryoablation (with temperatures of −40°C to −45°C for 90 seconds) were analyzed by angiography immediately and at 1 and 3 months in five animals. Pathologic recanalization and fibrosis was assessed at 3 months with use of a qualitative scoring system. Findings were compared with Mann-Whitney tests. RESULTS Recanalization after coil occlusion occurred in 50% and 60% of cases with cryoablation at 1 and 3 months, respectively, compared with 100% without ablation ( P = .012 and P = .029). There was no significant difference in pathologic scores ( P = .348). The brachial plexus in the vicinity of vertebral arteries was injured by cryotherapy in three animals in which an ipsilateral neurologic deficit developed. CONCLUSIONS Cryotherapy was moderately effective in the prevention of recanalization after coil occlusion. Deep nerve injury was excessive with the protocol used in the present study.

Recanalization after coil occlusion is a concern for long-term results of endovascular treatment. Knowledge of molecular events following coil occlusion and recanalization could help design specific strategies to promote permanent occlusion. Platinum coils were implanted into canine maxillary, vertebral or lingual arteries. Coil occlusion (treatment 1), routinely followed by recanalization was compared with two strategies to prevent recanalization: beta radiation using 32P coils (treatment 2) and endothelial denudation, using an endovascular device, followed by coil occlusion (treatment 3). The evolution of initial complete occlusions was followed by angiography and pathology at three months. Levels of messenger RNA of vWF (von Willebrand factor), SMA (smooth muscle actin), CD14, CD31 (or PECAM-1: Platelet Endothelial Cell Adhesion Molecule-1), PDGFBB (platelet-derived growth factor), TGF-b1 (transforming growth factor), MCP-1 (macrophage chemoattractant protein), Angiopoietins, Metalloproteinases-9, 14 and inhibitors (TIMP-2, 4) were followed by Reverse Transcription and Polymerase Chain Reaction (RT-PCR). Analyses were performed one, four, seven and 14 days after coiling, and levels of expression after the three treatments were compared using ANOVA s. Intact arteries treated with platinum coils routinely recanalize (100%), but arteries treated by denudation and coiling or with radioactive coils recanalize in only 17% and 4% respectively (P Recanalization is associated with early vWF expression, perhaps reflecting the development of endothelialized channels through thrombus formed after coil occlusion.

Endovascular coiling can improve the outcome of patients with ruptured intracranial aneurysms, but angiographic recurrences are frequent compared to surgical clipping. New coils or devices have been introduced to improve long-term results of endovascular treatment but none have been the object of a valid clinical trial. We have proposed a multicentric randomized double-blind study comparing radioactive and standard coil occlusion of aneurysms. The purpose of this article is to review issues that are specific to the design of clinical trials to assess embolic agents that could improve the long-term efficacy of endovascular treatment of intracranial aneurysms. The proposed trial is a randomized, multi-center, prospective, controlled trial comparing the new generation coils to standard platinum coils. Blinding, if at all possible, is preferable to minimize bias, at least for follow-up angiographic studies that should cover a period of 18 months. All patients with an intracranial aneurysm eligible for endovascular treatment would be proposed to participate. The study would enrol approximately 500 patients equally divided between the two groups, recruited within two years, to demonstrate a decrease in the recurrence rate, the primary outcome measure, from 20% to 10%. Secondary outcome measures should assure that complications, initial clinical and angiographic results remain unchanged. Independent data safety and monitoring committees are crucial to the credibility of trials and to ensure scientific rigor and objectivity. The scientific demonstration of an improved long-term efficacy, without significant compromise regarding safety, is mandatory before considering the widespread use of a new embolic device for the endovascular treatment of aneurysms.

Objective We developed an animal model to evaluate vascular trauma induced by endovascular devices that are proposed for the treatment of cerebrovascular diseases. Methods The model was constructed in six domestic swine by elongating the common carotid artery using interpositional grafts. Balloon catheters (n = 3), stents (n = 2), and a snare were tested 9 to 13 days after surgery. Device performance was evaluated by angiography, macroscopic photography, and histopathological examination. Results Animals tolerated the surgical procedure well, and artificial siphons were thought to provide realistic conditions for device testing. Balloon catheters induced minimal trauma, whereas coronary stents caused severe spasm or thrombosis and extensive macroscopic changes. Conclusion Construction of an in vivo siphon model is feasible and potentially useful for testing neurovascular devices.

Background and Purpose— Beta radiation prevents recanalization after coil embolization. We sought to determine the effects of varying coil caliber, length, activity of 32 P per centimeter of coil or per volume, and spatial distribution of coils on recanalization. Methods— We studied the angiographic evolution of 81 canine maxillary, cervical, and vertebral arteries implanted with a variety of nonradioactive (n=29 arteries) or radioactive (n=52) devices. We compared 1- or 2-caliber 0.015 or 0.010 coils ion-implanted or not with 3 different activity levels (0.05 to 0.08, 0.06 to 0.12, 0.18 to 0.32 μCi/cm) of 32 P and totaling 4, 8, and 16 cm in length for the same arterial volume. We also compared inhibition of recanalization by beta radiation delivered by stents, after coil occlusion proximal to or within the stent, with that delivered by coils placed within nonradioactive stents. We finally studied the angiographic evolution of canine lateral wall carotid aneurysms treated with 1 or 2 stents of various activity levels positioned inside the parent artery across the neck. Animals were killed at 4 and 12 weeks for macroscopic photography and pathological examination. Results— All arteries (29 of 29) occluded with nonradioactive devices were recanalized, while 49 of 52 arteries (94%) implanted with 32 P devices were occluded at 4 weeks. All aneurysms treated with stents, radioactive or not, demonstrated residual filling of the sac or of channels leading to the aneurysms at follow-up angiography at 4 weeks. Conclusions— The recanalization process found in the canine arterial occlusion model is minimally affected by coil caliber, number, and length or packing density. Beta radiation reliably inhibits this process, but thrombosis is an essential condition for the efficacy of a radioactive coil strategy.

Background and Purpose — We sought to investigate the role of the endothelial lining in aneurysmal persistence and recurrence after endovascular treatment of aneurysms. Methods — Bilateral venous pouch canine carotid aneurysms were studied by angiography and pathology 1, 2, and 3 weeks after intraoperative collagen sponge embolization, coated or not coated with fibrinogen (n=15). In 12 dogs the endothelial lining of one aneurysm was removed before embolization, and results were compared with a control aneurysm after bilateral sponge embolization. In 4 animals embolization with a sponge covered with endothelium was compared with treatment with a sponge covered with adventitia. In 4 animals an inverted venous pouch aneurysm embolized with an adventitia-covered sponge was compared with a normal aneurysm embolized with an endothelialized sponge. In 3 animals inverted venous pouch aneurysms were embolized with a sponge covered or not covered with endothelium. Control aneurysms (n=3 or 4 each) included untreated normal, inverted, and de-endothelialized venous pouch aneurysms. Angiographic results at 3 weeks were compared by Wilcoxon’s test. Results — Endothelialization of the clot that forms on the sponge was complete at 1 week, forming clefts that developed into recurrences. Reversed or de-endothelialized aneurysms spontaneously thrombosed, while normal venous pouch aneurysms remained patent for at least 3 weeks. The addition of fibrinogen, endothelium, or adventitia to the sponges did not prevent recurrences, which occurred routinely after embolization of endothelialized aneurysm. De-endothelialization of the aneurysmal wall improved angiographic results at 3 weeks ( P =0.02), while reversing the venous pouch before embolization led to complete healing ( P =0.003). Conclusions — The endothelial lining is essential to the persistence of residual lesions. Early endothelial invasion of the clot leads to recanalization and recurrences after embolization of aneurysms. This observation provides new opportunities to improve results of endovascular treatment of aneurysms.

BACKGROUND AND PURPOSE: Angiographic results are commonly used as surrogate markers of the success of intra-arterial therapies for acute stroke. Inter- and intraobserver agreement in judging angiographic results remain poorly characterized. Our goal was to assess 2 commonly used revascularization scales. MATERIALS AND METHODS: A portfolio of 148 pre- and post treatment images of 37 cases of proximal anterior circulation occlusions was electronically sent to 12 expert observers who were asked to grade treatment outcomes according to recanalization (of arterial occlusive lesion) or reperfusion (TICI) scales. Three expert observers had to score treatment outcomes by using a similar portfolio of 32 patients or when they had full access to all angiographic data, twice for each method 3–12 months apart. Results were analyzed by using κ statistics. RESULTS: Agreement among 9 responding observers was moderate for both the TICI (κ = 0.45 ± 0.01) and arterial occlusive lesion (κ = 0.39 ± 0.16) scales. Agreement was similar (moderate) when 3 observers had access to a portfolio (κ = 0.59 ± 0.06 and 0.49 ± 0.07, respectively) or to the full angiographic data (κ = 0.54 ± 0.06 and 0.59 ± 0.07, respectively). Intraobserver agreement was “fair to moderate” for both methods. Interobserver agreement became “substantial” (>0.6) when outcomes were dichotomized into “success” (TICI 2b, 3; arterial occlusive lesion II, III or “failure”; the results were judged more favorably when the arterial occlusive lesion rather than the TICI scale was used. CONCLUSIONS: There is an important variability in the assessment of angiographic outcomes of endovascular treatments, invalidating comparisons among publications. A simple dichotomous judgment can be used as a surrogate outcome when treatments are assessed by the same observers in randomized trials.

Innovations in endovascular tools have permitted an increasingly broad range of neurovascular lesions to be treated via minimally invasive methods. However, some device modifications may carry additional risks, not immediately apparent to operators. A patient with a symptomatic, partially thrombosed basilar apex aneurysm was allocated balloon-assisted coiling. Attempts were made to place a microwire across the basilar apex through the posterior communicating artery. Overlapping courses of the posterior cerebral and posterior choroidal arteries on the roadmap images were not recognized and a flanged-tip microwire was inadvertently advanced deep into the choroidal artery. Following the wire with a microcatheter led to binding of arterial tissue within the microcatheter. Removing the wire led to an avulsion of the choroidal artery and a severe hemorrhagic complication which proved fatal. Tissue was identified on the tip of the guidewire. Pathology showed layers of vascular tissue within the laser-cut flanges of the distal wire tip. A similar complication, also fatal, occurred during balloon angioplasty of a distal vertebral artery, when an exchange wire was accidently introduced into a perforator from a posterior cerebral artery. Ex vivo catheterization of distal mesenteric arterial branches showed that the wall of small arteries can be entrapped by laser-cut, flanged, but not by smooth guidewire tips. Microwires with a flanged instead of smooth distal tip, when placed into small caliber vessels, may cause hemorrhagic complications from avulsions.

BACKGROUND AND PURPOSE: Endovascular treatment of wide-neck bifurcation aneurysms often results in incomplete occlusion or aneurysm recurrence. The goals of this study were to compare results of coil embolization with or without the assistance of self-expandable stents and to examine how stents may influence neointima formation. MATERIALS AND METHODS: Wide-neck bifurcation aneurysms were constructed in 24 animals and, after 4–6 weeks, were randomly allocated to 1 of 5 groups: 1) coil embolization using the assistance of 1 braided stent ( n = 5); 2) coil embolization using the assistance of 2 braided stents in a Y configuration ( n = 5); 3) coil embolization without stent assistance ( n = 6); 4) Y-stenting alone ( n = 4); and 5) untreated controls ( n = 4). Angiographic results were compared at baseline and at 12 weeks, by using an ordinal scale. Neointima formation at the neck at 12 weeks was compared among groups by using a semiquantitative grading scale. Bench studies were performed to assess stent porosities. RESULTS: Initial angiographic results were improved with single stent–assisted coiling compared with simple coiling ( P = .013). Angiographic results at 12 weeks were improved with any stent assistance ( P = .014). Neointimal closure of the aneurysm neck was similar with or without stent assistance ( P = .908), with neointima covering coil loops but rarely stent struts. Y-stent placement alone had no therapeutic effect. Bench studies showed that porosities can be decreased with stent compaction, but a relatively stable porous transition zone was a limiting factor. CONCLUSIONS: Stent-assisted coiling may improve results of embolization by allowing more complete initial coiling, but these high-porosity stents did not provide a scaffold for more complete neointimal closure of aneurysms.

BACKGROUND AND PURPOSE: The relationship between aneurysm dimensions, flow, thrombosis, and rupture remains poorly understood. We attempted to clarify this relationship by exploring various swine aneurysm models. MATERIALS AND METHODS: Bilateral carotid aneurysms were constructed according to 3 protocols in 24 animals: small aneurysms with wide necks (group 1; n = 6 animals); small aneurysms with small necks (group 2; n = 4 animals), and giant aneurysms with large necks (group 3; n = 14 animals). Group 3 included 3 subgroups, related to testing the model in various experimental conditions: The neck was clipped in 3 animals; venous pouches lacked an endothelial lining in 4 animals; and 7 were control animals. Animals were followed until rupture, or for 1–4 weeks. Angiography was performed postoperatively and before euthanasia. We studied lesion pathology, paying attention to thrombosis, recanalization, wall composition, and perianeurysmal hemorrhage. RESULTS: Groups differed significantly in aneurysm dimensions and aspect ratio (P = .002). Ruptures occurred more frequently in animals with untreated giant aneurysms (7/7) than in animals with small wide-neck (0/6) or small-neck (2/4) aneurysms (P = .002). Ruptures occurred only in animals with thrombosed aneurysms. Lesions lacking an endothelial lining and 5 of 6 clipped venous pouches thrombosed but did not rupture. One giant lesion ruptured despite complete clipping. The wall was deficient in α-actin and was infiltrated with inflammatory cells and erythrocytes in all thrombosed cases, ruptured or not. Ruptures were associated with recanalizing channels in 9 of 10 cases. CONCLUSIONS: Thrombosis, inflammation, and recanalization may precipitate aneurysmal ruptures in a swine model

Recanalization after coil occlusion is a concern for long-term results of endovascular treatment. Knowledge of molecular events following coil occlusion and recanalization could help design specific strategies to promote permanent occlusion. Platinum coils were implanted into canine maxillary, vertebral or lingual arteries. Coil occlusion (treatment 1), routinely followed by recanalization was compared with two strategies to prevent recanalization: beta radiation using 32P coils (treatment 2) and endothelial denudation, using an endovascular device, followed by coil occlusion (treatment 3). The evolution of initial complete occlusions was followed by angiography and pathology at three months. Levels of messenger RNA of vWF (von Willebrand factor), SMA (smooth muscle actin), CD14, CD31 (or PECAM-1: Platelet Endothelial Cell Adhesion Molecule-1), PDGF-BB (platelet-derived growth factor), TGF-b1 (transforming growth factor), MCP-1 (macrophage chemoattractant protein), Angiopoietins, Metalloproteinases-9,14 and inhibitors (TIMP-2, 4) were followed by Reverse Transcription and Polymerase Chain Reaction (RT-PCR). Analyses were performed one, four, seven and 14 days after coiling, and levels of expression after the three treatments were compared using ANOVAs. Intact arteries treated with platinum coils routinely recanalize (100%), but arteries treated by denudation and coiling or with radioactive coils recanalize in only 17% and 4% respectively (P

Background: Flow diverters (FDs) are increasingly used for bifurcation aneurysms. Failure of aneurysm occlusion may be caused by residual flow maintaining patency of the jailed branch along with the aneurysm. Methods: Sixteen wide-necked lingual-carotid artery bifurcation aneurysms were created in 8 canines. Patent aneurysms were randomly allocated 4 weeks later to flow diversion combined with jailed branch occlusion using coils and/or Onyx (n=6) or flow diversion alone (n=8). Angiographic results of aneurysm occlusion at three months were scored using an ordinal scale. Pathology specimens were photographed and neointimal coverage estimated. Results: Fourteen aneurysms were patent at one month. FD deployment was successful in all cases, but at 3 month follow-up, 3 devices had prolapsed into the aneurysm. None of the bifurcation aneurysms treated with FD alone were occluded at 3 months. Endovascular branch occlusion combined with flow diversion significantly improved aneurysm occlusion rates (median angiographic score of 2) compared to flow diversion alone (median score of 0: P=0.0137). Flow-limiting parent vessel stenosis was not observed in any arteries. Devices were covered with thick neointima in most cases. Conclusions: Treatment failures following flow diversion of bifurcation aneurysms can be caused by persistent flow to the jailed branch. Branch occlusion combined with flow diversion may improve angiographic occlusion of canine aneurysms.

Background and purpose Surgical clipping of unruptured intracranial aneurysms (UIAs) has recently been challenged by the emergence of endovascular treatment. We performed an updated systematic review and meta-analysis on the surgical treatment of UIAs, in an attempt to determine the aneurysm occlusion rates and safety of surgery in the modern era. Methods A detailed protocol was developed prior to conducting the review according to the Cochrane Collaboration guidelines. Electronic databases spanning January 1990–April 2011 were searched, complemented by hand searching. Heterogeneity was assessed using I2, and publication bias with funnel plots. Surgical mortality and morbidity were analysed with weighted random effect models. Results 60 studies with 9845 patients harbouring 10 845 aneurysms were included. Mortality occurred in 157 patients (1.7%; 99% CI 0.9% to 3.0%; I2=82%). Unfavourable outcomes, including death, occurred in 692 patients (6.7%; 99% CI 4.9% to 9.0%; I2=85%). Morbidity rates were significantly greater in higher quality studies, and with large or posterior circulation aneurysms. Reported morbidity rates decreased over time. Studies were generally of poor quality; funnel plots showed heterogeneous results and publication bias, and data on aneurysm occlusion rates were scant. Conclusions In studies published between 1990 and 2011, clipping of UIAs was associated with 1.7% mortality and 6.7% overall morbidity. The reputed durability of clipping has not been rigorously documented. Due to the quality of the included studies, the available literature cannot properly guide clinical decisions.

High-porosity (HP) and flow-diverting (FD) stents are increasingly used to treat intracranial aneurysms. In vivo device deformations and their impact on the porosity of the segment of device lying over the aneurysm neck remain inadequately characterized.Porosities of different braided FDs were studied in straight and 90° curved glass tubes. In vivo, 11 experimental lateral wall aneurysms were treated with FD (n = 7) or HP (n = 4) stents. At 3 months, the segment of FDs and HP stents over the aneurysm neck was analyzed, paying attention to changes in device diameter, metallic porosity, and neointimal closure of pores over the aneurysm or branch ostia. Device deformations were reproduced with benchtop experiments.In 90° curved tubes, FD porosity was higher (P = 0.025) and pore density was lower (P = 0.01) on convex compared to concave surfaces, but variations remained within 5-10 %. After in vivo deployment, a spindle-shaped deformation of FDs occurred, with focal expansion at the level of the aneurysm neck (P = 0.004). This deformation translated into an accordion-like distribution of stent struts across the aneurysm neck, where porosity was not uniform. The midsection of the aneurysm ostium had more metal coverage than adjacent ostial areas (P = 0.002). Mean porosity over the aneurysm neck was 78 ± 9.4 and 32.6 ± 12.1 % for HP and FD stents, respectively (P = 0.008), decreasing to 13.0 ± 10.1 and 1.4 ± 0.6 % (P = 0.022) following neointimal coverage, respectively. Spindle-shaped deformations and accordion effects were reproduced with benchtop manipulations; fluctuations in porosity and diameter changes correlated closely (R = 0.81; P = 0.005).Alterations in porosity may occur following in vivo implantation.

Flow diverters (FDs) are increasingly used to treat complex intracranial aneurysms, but preclinical studies that could guide clinical applications are lacking. The authors designed a modular aneurysm model in canines to address this problem.Three variants of one modular aneurysm model were constructed in 21 animals. Sidewall (n=5), curved sidewall (n=5), and end-wall bifurcation (n=7) aneurysms were treated with prototype 36-wire FDs. Four more end-wall bifurcation aneurysms were treated with prototype 48-wire lower-porosity FDs. Angiographic results postimplantation and at 3 months were scored with an ordinal scale. Animals were euthanized at 3 (n=17) or 6 (n=3) months, and the FD covering the aneurysm ostium was photographed to analyze metallic porosity and amount of neointima formation.Straight sidewall aneurysms were better occluded than curved sidewall and end-wall bifurcation aneurysms at the 3-month angiography follow-up (p=0.010). Flow diverters failed to occlude curved sidewall aneurysms (n=0/5) and all but one (n=1/7) end-wall bifurcation aneurysm. Angiographic results were no better (n=0/4) using a 48-wire FD (p=0.788). Branches jailed by the FD (n=16) remained patent in all cases. Metallic porosity was decreased (p=0.014) and neointimal closure of the aneurysm ostium was more complete (p=0.040) in sidewall aneurysms than in curved or bifurcation variants of the model.Flow diverters may succeed in treating straight sidewall aneurysms, but the same device repeatedly fails to occlude curved sidewall and end-wall bifurcation aneurysms. In vivo studies can be designed to test basic principles that, once validated, may serve to guide clinical use of new devices.

BACKGROUND AND PURPOSE: FDs are the latest, most promising tool to treat giant and complex aneurysms. Currently available experimental aneurysm models do not reproduce the potential clinical difficulties of treating these lesions with FDs. MATERIALS AND METHODS: Six large or giant canine fusiform aneurysms were created on the distal carotid arteries of 4 animals. Four of the aneurysms had multiple arterial branches originating from the aneurysm; 2 other aneurysms had all branches clipped at the time of aneurysm construction. Aneurysms were treated with multiple telescoping prototype flow-diverting stents (total of 15 FDs). Angiography was carried out before and immediately after implantation, at 2 weeks, and immediately before sacrifice at 12 weeks. Macroscopic photography of specimens was performed, followed by biopsies of selected regions of the tissue formed on the surface of FDs. RESULTS: Technical or device-related difficulties occurred in 2 of 6 aneurysm treatments. Fusiform aneurysms with branches intact remained widely patent (mean angiographic score, 3), whereas aneurysms with clipped branches had only small residua (mean angiographic score, 1) at 12 weeks. The presence of very small defects in neointima formation on the surface of FDs, or leaks, was sufficient for residual filling of the aneurysms, which served as reservoirs to feed branches. CONCLUSIONS: Experimental canine fusiform carotid aneurysms may reproduce many of the difficulties associated with the treatment of giant aneurysms and could be appropriate for preclinical testing of FD stents.

The trial on endovascular management of unruptured intracranial aneurysms (TEAM), a prospective randomized trial comparing coiling and conservative management, initiated in September 2006, was stopped in June 2009 because of poor recruitment (80 patients). Aspects of the trial design that may have contributed to this failure are reviewed in the hope of identifying better ways to successfully complete this special type of pragmatic trial which seeks to test two strategies that are in routine clinical use. Cultural, conceptual and bureaucratic hurdles and difficulties obstruct all trials. These obstacles are however particularly misplaced when the trial aims to identify what a good medical practice should be. A clean separation between research and practice, with diverging ethical and scientific requirements, has been enforced for decades, but it cannot work when care needs to be provided in the presence of pervasive uncertainty. Hence valid and robust scientific methods need to be legitimately re-integrated into clinical practice when reliable knowledge is in want. A special status should be reserved for what we would call 'clinical care trials', if we are to practice in a transparent and prospective fashion a medicine that leads to demonstrably better patient outcomes.

Matrix metalloproteinase (MMP)-9 plays various roles in vascular healing and angiogenesis. This study was conducted to determine if MMP-9 is involved in healing or recanalization after therapeutic occlusion of arteries or aneurysms.Angiographic and pathologic changes were investigated in canine bilateral venous pouch carotid aneurysms embolized with gelatin sponges with or without previous endothelial denudation, a procedure that can prevent recanalization. To assess a potential role of MMP-9, messenger RNA (mRNA) and protein were compared in denuded and nondenuded aneurysms 4, 7, and 14 days after embolization. To assess if MMP-9 is essential to arterial recanalization, transmyocardial angiography and pathologic findings were compared 14 days after carotid occlusion with platinum coils in MMP-9-knockout and wild-type mice.Denudation of the endothelial lining led to improved angiographic results at 3 weeks (P.001). Neointimal closure of the aneurysm neck was more complete in denuded versus nondenuded aneurysms. Denudation was followed by a decrease in MMP-9 mRNA (86%, P.05) and protein (30%, P.05) 7 days after embolization and a decrease in von Willebrand factor compared with nondenuded aneurysms. MMP-9 immunostaining of axial sections from embolized aneurysms confirmed MMP-9-positive endothelialized clefts, which were absent in denuded aneurysms. Transmyocardial angiography and pathologic examination showed recanalization of one of nine coiled carotid arteries of MMP-9-knockout mice, compared with five of seven controls (P = .035).MMP-9 may play a role in recanalization of arteries after coil occlusion and in recurrences after sponge embolization of aneurysms.

Intracranial stents are increasingly used in the endovascular treatment of aneurysms, but very little is known regarding their effect on the cellular and molecular evolution of aneurysms. Bilateral venous pouch lateral wall carotid aneurysms were created in 20 dogs. All dogs then underwent angiography and balloon-expandable stenting of one aneurysm four to six weeks later. Fifteen dogs underwent aneurysm harvesting at one day (n=3), four days (n=4), seven days (n=3), and 14 days (n=5) for mRNA expression analysis, using axial sections taken from the aneurysm neck and fundus for RT-PCR amplification of four cytokines or growth factors: TNF-a, TGF-b1, MCP-1, and PDGF-BB; two adhesion molecules: VCAM-1 and PECAM-1; five matrix modifying agents; MMP-2, 9, TIMPs 1, 3, 4, and two cellular markers: CD34 and a-SMA. Five other dogs, sacrificed at 12 weeks, were examined for extent of filling of the aneurysm neck with organized tissue and for neointima formation at the aneurysm ostium. Angiography was performed prior to sacrifice in all animals, and compared with initial studies. Eleven out of 20 stented aneurysms showed a favorable angiographic evolution, while none of the 20 non-stented aneurysms improved (p=0.001). Pathology showed partially occluded aneurysms, with neointima formation around the stent struts. Observed trends in mRNA expression, that stenting increased expression of genes involved in organization and neointima formation, agreed with experimental hypotheses, but differences between stented and non-stented aneurysms did not reach statistical significance. Parent vessel stenting was associated with angiographic improvement of aneurysm appearance. Modifications in mRNA expression patterns following stenting deserve further study to better establish potential molecular targets to promote aneurysm healing.