Search

BACKGROUND AND PURPOSE Delayed cerebral ischemia (DCI) and angiographic vasospasm following subarachnoid hemorrhage (SAH) have been associated for more than 50years. We aimed to examine whether the knowledge gained by theoretical research on vasospasm has actually translated into better patient outcomes in practice. METHODS This is a narrative review of the concept of vasospasm as a cause of DCI after SAH. We discuss recent studies that have assessed the accuracy and reliability of the diagnostic tests (transcranial Doppler ultrasound [TCD], CT angiography, and catheter angiography), which are used to identify SAH patients at-risk of DCI. RESULTS Both the diagnostic accuracy of TCD and the reliability of CT angiography to identify patients in severe vasospasm are poor. For the gold standard catheter angiography, the repeatability of the diagnosis of vasospasm, made by multiple raters, is only fair. Interventions on angiographic vasospasm have never been proven to improve patient outcomes. A pragmatic trial integrating the meaning of the diagnosis of vasospasm into a study protocol that assesses the value of endovascular interventions in the prevention of DCI after SAH seems to be in order. Such a trial could provide a pragmatic definition of clinically meaningful vasospasm. CONCLUSION We must move beyond research conceived as an enterprise aiming to acquire theoretical knowledge to one where research is integrated into clinical practice to improve clinical outcomes in real time.

The Comprehensive Aneurysm Management (CAM) study is a pragmatic trial designed to manage unruptured intracranial aneurysm (UIA) patients within a care research framework.CAM is an all-inclusive study. Management options are allocated according to an algorithm combining pre-randomization and clinical judgment. Eligible patients are offered 1:1 randomized allocation of intervention versus conservative management and 1:1 randomization allocation of surgical versus endovascular treatment. Ineligible patients are registered. The primary outcome is survival without dependency (modified Rankin Scale score3) at 10 years. All UIA patients at 1 center are reported.Between February 2020 and July 2021, 403 UIA patients were recruited: 179 (44%) in one of the randomized controlled trials (RCTs) and 224 (56%) in one of the registries. Conservative management was recommended for 205 of 403 patients (51%); of 198 (49%) patients considered for curative treatment, 159 (80%) were randomly allocated conservative (n = 81) or curative treatment (n = 78). These patients were younger and had larger aneurysms than those in the observation registry (P = 0.004). In 39 of 198 patients (20%), conservative management was not considered reasonable (17 patients were recommended endovascular, 2 surgery, and 20 the RCT comparing endovascular with surgical treatment). In total, 70 patients were recruited in the RCT comparing surgery and endovascular treatment. After informed discussion at time of consent, 141 of 159 patients (89%) agreed with the randomly allocated management plan, while 11% crossed over to the alternative management option.CAM was successfully integrated into routine practice. Meaningful conclusions can be obtained if multiple centers actively participate in the trial.

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 Pragmatic care trials have been designed to provide optimal neurovascular care in the presence of uncertainty. The feasibility, benefits, and drawbacks of using this novel approach remain unknown. Methods We report the progress of 9 randomized trials integrated into routine practice to guide the endovascular or surgical treatment of intracranial aneurysms, arteriovenous malformations, and acute stroke. We review the criticisms and commentaries we have received and discuss the corresponding ethical and scientific concepts that need to be revised to practice outcome-based neurovascular care. Results Pragmatic care trials were used to address long standing dilemmas regarding rival management options or to offer innovative treatments for 1212 neurovascular patients recruited in an elective or acute care context. Adopting care trial methodology had an immediate impact on clinical practice, replacing unrepeatable treatment decisions by 1:1 randomized allocation whenever reliable knowledge about best management was not available. The care trial approach transformed unfounded medical practice into verifiable outcome-based medical care and reserved authoritative recommendations for care options that had previously been validated. Criticisms we have encountered include mainly the pragmatic trial design choices, with insufficient selection of patients and clinicians, too-flexible protocols, lack of funding and feasibility. Conclusion Care trials can be integrated into neurovascular practice. Although they remain a work in progress, the approach curtails the practice of unverifiable medicine and offers patients optimal care in the presence of uncertainty.

Posterior fossa arteriovenous malformations (pfAVMs) can be challenging lesions to manage. AVMs in this location may have distinct features compared with supratentorial AVMs. Our aim was to systematically review the literature on the presenting characteristics of pfAVMs and compare clinical and angiographic outcomes after the various types of treatment employed. The review was conducted according to the Cochrane Collaboration guidelines. Electronic databases from 1900 to March 2018 were searched and complemented by hand-searching and cross-referencing. Articles were categorized into (i) AVM studies that included those in the posterior fossa, (ii) those that focused exclusively on pfAVM, and (iii) those that further specified a cerebellar or brainstem location of the AVM. Seventy-seven articles with 4512 pfAVM patients were retained for analyses. Compared with historical supratentorial controls, pfAVMs were reported to more frequently present with rupture, to more commonly have associated arterial aneurysms, and to more frequently lead to poor clinical and angiographic outcomes. The quality of the literature and lack of standardization of outcome reporting precluded performing a meta-analysis on the results of the various different treatment modalities. Posterior fossa AVMs may have some distinct features compared with supratentorial AVMs. The available reports on pfAVMs are not sufficiently standardized to provide reliable guidance for patient management decisions. This goal will require future studies to be multicentric and to focus on standardized, repeatable clinical and angiographic outcomes.

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.

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.

Background Wide-necked bifurcation aneurysms (WNBA) are a difficult subset of aneurysms to successfully repair endovascularly, and a number of treatment adjuncts have been designed to improve on the results of coiling, including stenting and flow diversion of the parent vessel. Surgical clipping is commonly performed for certain WNBAs, such as middle cerebral aneurysms, in some centres. Intra-saccular flow diversion (ISFD) using the Woven Endo-Bridge (WEB) or similar devices, has been developed as a new endovascular alternative to coiling for WNBAs. Meta-analyses of case series suggest satisfactory results, both in terms of safety and efficacy, but in the absence of randomized evidence, whether ISFD leads to better outcomes for patients with WNBA remains unknown. There is a need to offer ISFD within the context of a randomized care trial. Methods The proposed trial is a multicentre, randomized controlled care trial comparing ISFD and best conventional management option (surgical or endovascular), as determined by the treating physician prior to randomized allocation. At least 250 patients will be recruited in at least 10 centres over a four-year period, and followed for one year, to show that ISFD can increase the incidence of successful therapy from 75 to 90% of patients, defined as complete or near-complete occlusion of the aneurysm AND a good clinical outcome (mRS ≤ 2) at one year. The trial will be followed by an independent data safety monitoring committee to assure the safety of participants. Conclusion Introduction of intra-saccular flow diversion can be accomplished within a care trial context.

Background Randomized trials of commonly performed surgical interventions are notoriously difficult to conduct. The trial methodology may nevertheless be the best way to offer outcome-based neurovascular care in the presence of uncertainty. One obstacle to promoting such trials is the conventional prohibition of publication and dissemination of interim results as the trial progresses. Methods We review the scientific and statistical reasons against the publication of interim analyses as well as exceptions that can occur when 1 treatment is unexpectedly shown to be harmful or when the results of other trials have convincingly shown the comparative benefits of a new intervention. We also discuss the promotion of difficult surgical trials. Results Reasons to support the conventional ban on publication of interim results include control of statistical errors, prevention of invalid conclusions, and dissemination of false claims of equivalence of rival interventions. In the early phases of a trial, usually 1 treatment cannot be shown superior to the other. We believe, contrary to the received view, that a transparent report of the early progress of certain trials can be justified, even when interim results are inconclusive, to promote the recruitment of participating centers and the practice of a novel way to offer neurovascular care in the presence of uncertainty in the best medical interest of patients. Conclusions In our opinion, the early publication of inconclusive interim results may increase awareness of the feasibility of surgical care trials.

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 best management of unruptured intracranial aneurysms (UIAs) remains unknown, despite multiple observational studies. A randomized trial (RCT) is in order. Yet, a National Institute Neurological Disorders and Stroke workshop has once again proposed to use prospective observational studies (POS) of large databases to address such problems. Methods We review the historical misconceptions that have been associated with observations of UIAs and their treatments. We critically examine some recent methods that have been proposed to address shortcomings of observational studies. We finally review the ethical principles underlying the use of trial methods in the care of patients. Results Replacing RCTs with POS submits patients to management options that have never been proven beneficial, while making them involuntary research subjects of studies that are inevitably biased. A science of practice cannot be an outsider's examination of the behavior of clinicians incapable of questioning their practice. The thesis we propose is that a science of practice must not only eventually determine what best practice will be; It must engage agents involved in medical practice to transparently reveal the uncertainty that calls for management options to be offered under the guidance of declared and controlled care research, to optimize patient outcomes in spite of the uncertainty. Conclusion To use POS rather than RCTs in medical practice is to renege on scientific and ethical principles that characterize modern medicine. Instead, we must learn to integrate care research into our practice to provide optimal medical care in real time.

Background A sustained release microparticle formulation of nimodipine (EG-1962) was developed for treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH). Objective To assess safety, tolerability, and pharmacokinetics of intracisternal EG-1962 in an open-label, randomized, phase 2 study of up to 12 subjects. Methods Subjects were World Federation of Neurological Surgeons grades 1 to 2, modified Fisher grades 2 to 4, and underwent aneurysm clipping within 48 h of aSAH. EG-1962, containing 600 mg nimodipine, was administered into the basal cisterns. Outcome on the extended Glasgow Outcome Scale (eGOS), pharmacokinetics, delayed cerebral ischemia and infarction, rescue therapy, and safety were evaluated. Results The study was halted when a phase 3 study of intraventricular EG-1962 stopped because that study was unlikely to meet its primary endpoint. Six subjects were randomized (5 EG-1962 and 1 oral nimodipine). After 90-d follow-up, favorable outcome on the eGOS occurred in 1 of 5 EG-1962 and in the single oral nimodipine patient. Four EG-1962 and the oral nimodipine subject had angiographic vasospasm. One EG-1962 subject had delayed cerebral ischemia, and all subjects with angiographic vasospasm received rescue therapy except 1 EG-1962 patient. One subject treated with EG-1962 developed right internal carotid and middle cerebral artery narrowing 5 mo after placement of EG-1962, leading to occlusion and cerebral infarction. Pharmacokinetics showed similar plasma concentrations of nimodipine in both groups. Conclusion Angiographic vasospasm and unfavorable clinical outcome still occurred after placement of EG-1962. Internal carotid artery narrowing and occlusion after placement of EG-1962 in the basal cisterns has not been reported.

We would like to comment on the conclusions of the recent paper reporting the 3 year follow-up results of the Webcast studies1: ‘This analysis confirms the high safety profile of WEB…the great stability of aneurysm occlusion in 83.6% of aneurysms’. It is not easy to criticize a manuscript written by 17 experts, including many prominent leaders of the neurovascular field and several close friends, particularly one where superlatives (‘high safety’ and ‘great stability’) and ‘GCP’ (n=8) are used repeatedly. Yet, as true friends, we must tell the ‘ugly truth’: 10 years after its introduction, the evidence supporting the use of WEB in the treatment of aneurysms (mainly small unruptured aneurysms) is weak; a case series of 100 or so highly selected patients, recruited in …

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.

OBJECTIVEEndovascular treatment of aneurysms may result in incomplete initial occlusion and aneurysm recurrence at angiographic follow-up studies. This study aimed to assess the feasibility and efficacy of bipolar radiofrequency ablation (RFA) of aneurysm remnants after coil embolization.METHODSBipolar RFA was accomplished using the coil mass as 1 electrode, while the second electrode was a stent placed across the aneurysmal neck. After preliminary experiments and protocol approval from the Animal Care committee, wide-necked bifurcation aneurysms were constructed in 24 animals. Aneurysms were allocated to 1 of 3 groups: partial intraoperative coil embolization, followed by RFA (n = 12; treated group) or without RFA (n = 6; control group 1); or attempted complete endovascular coil embolization 2–4 weeks later (n = 6; control group 2). Angiographic results were compared at baseline, immediately after RFA, and at 12 weeks, using an ordinal scale. Pathological results and neointima formation at the neck were compared using a semiquantitative grading scale.RESULTSBipolar RFA was able to reliably target the aneurysm neck when the coil mass and stent were used as electrodes. RFA improved angiographic results immediately after partial coiling (p = 0.0024). Two RFA-related complications occurred, involving transient occlusion of 1 carotid artery and 1 hemorrhage from an adventitial arterial blister. At 12 weeks, angiographic results were improved with RFA (median score of 0), when compared with controls (median score of 2; p = 0.0013). Neointimal closure of the aneurysm neck was better with RFA compared with controls (p = 0.0003).CONCLUSIONSBipolar RFA can improve results of embolization in experimental models by selectively ablating residual lesions after coil embolization.

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.

OBJECTIVE The ARUBA study (A Randomized Trial of Unruptured Brain Arteriovenous Malformations [AVMs]) on unruptured brain AVMs has been the object of comments and editorials. In the present study the authors aim to systematically review critiques, discuss design issues, and propose a framework for future trials. METHODS The authors performed a systematic review of the French and English literature on the ARUBA study published between January 2006 and February 2015. The electronic search, including the Cochrane Library, MEDLINE (PubMed and Ovid), CINAHL, and EMBASE databases, was complemented by hand searching and cross-referencing. The comments were categorized as items related to the design, the conduct, and the analysis and interpretation of the trial. RESULTS Thirty-one articles or letters were identified. The pragmatic design, with heterogeneity of patients and lack of standardization of the treatment arm, were frequently stated concerns. The choice of outcome measures was repeatedly criticized. During the trial, low enrollment rates, selection bias, and premature interruption of enrollment were frequent comments. The short follow-up period, the lack of subgroup analyses, the lack of details on the results of the various treatments, and a contentious interpretation of results were noted at the analysis stage. A fundamental problem was the primary hypothesis testing conservative management. The authors believe that other trials are needed. Future trials could be pragmatic, test interventions stratified at the time of randomization, and look for long-term, hard clinical outcomes in a large number of patients. CONCLUSIONS In the authors' view, the ARUBA trial is a turning point in the history of brain AVM management; future trials should aim at integrating trial methodology and clinical care in the presence of uncertainty.

BACKGROUND AND PURPOSE: Some patients are at high risk of aneurysm recurrence after endovascular treatment: patients with large aneurysms (Patients Prone to Recurrence After Endovascular Treatment PRET-1) or with aneurysms that have previously recurred after coiling (PRET-2). We aimed to establish whether the use of hydrogel coils improved efficacy outcomes compared with bare platinum coils. MATERIALS AND METHODS: PRET was an investigator-led, pragmatic, multicenter, parallel, randomized (1:1) trial. Randomized allocation was performed separately for patients in PRET-1 and PRET-2, by using a Web-based platform ensuring concealed allocation. The primary outcome was a composite of a residual/recurrent aneurysm, adjudicated by a blinded core laboratory, or retreatment, intracranial bleeding, or mass effect during the 18-month follow-up. Secondary outcomes included adverse events, mortality, and morbidity (mRS > 2). The hypothesis was that hydrogel would decrease the primary outcome from 50% to 30% at 18 months, necessitating 125 patients per group (500 for PRET-1 and PRET-2). RESULTS: The trial was stopped once 250 patients in PRET-1 and 197 in PRET-2 had been recruited because of slow accrual. A poor primary outcome occurred in 44.4% (95% CI, 35.5%–53.2%) of those in PRET-1 allocated to platinum compared with 52.5% (95% CI, 43.4%–61.6%) of patients allocated to hydrogel (OR, 1.387; 95% CI, 0.838–2.295; P = .20) and in 49.0% (95% CI, 38.8%–59.1%) in PRET-2 allocated to platinum compared with 42.1% (95% CI, 32.0%–52.2%) allocated to hydrogel (OR, 0.959; 95% CI, 0.428–1.342; P = .34). Adverse events and morbidity were similar. There were 3.6% deaths (1.4% platinum, 5.9% hydrogel; P = .011). CONCLUSIONS: Coiling of large and recurrent aneurysms is safe but often poorly effective according to angiographic results. Hydrogel coiling was not shown to be better than platinum.

Background Endovascular coil embolization of cerebral aneurysms is an effective treatment for the prevention of aneurysm rebleeding after subarachnoid hemorrhage. It is also often used in unruptured aneurysms, but it is associated with aneurysm remnants and recurrences in up to 20%–33% of patients. We hypothesized that better aneurysm occlusion rates can be achieved with coils of larger caliber. Methods The Does Embolization with Larger coils lead to better Treatment of Aneurysms (DELTA) trial is an investigator-initiated, multicenter, prospective, randomized, controlled clinical trial. To test the hypothesis that 15-caliber coiling systems are superior to 10-caliber coils, 564 patients with aneurysms measuring 4–12 mm will be randomized 1:1 to embolization with either 10-caliber coils exclusively (control group) or the highest safely achievable proportion of 15-caliber coils (intervention group). The primary efficacy endpoint of the trial is the occurrence of a major recurrence or a residual aneurysm at one year. A pilot phase of 165 patients will be conducted to verify feasibility of the coiling strategy, compliance to treatment allocation, safety of a 15-caliber platinum coil embolization strategy, recruitment rates, and the capacity to improve packing density. Discussion The DELTA trial will test the hypothesis that the use of coils of larger caliber can improve angiographic results of endovascular coiling.

Objective The management of unruptured and ruptured brain arteriovenous malformations (AVMs) remains controversial. The Treatment of Brain AVM Study (TOBAS) was designed to assess curative treatments in the management of AVMs. The purpose of our study is to provide a care trial context to brain AVM patients. Methods TOBAS is a pragmatic, prospective study including 2 randomized controlled trials and a registry. All AVM patients can be recruited. The preferred management modality will be predetermined prior to randomization by the team based on clinical judgment. Patients eligible for both conservative and interventional management will be randomly allocated conservative or curative treatment. Randomization will be stratified by a treatment modality (surgery, radiosurgery or embolization) and minimized according to a history of previous rupture and Spetzler-Martin grade. A second randomization will allocate eligible patients to embolization/no embolization prior to surgery or radiosurgery. The primary outcome of the study is death (any cause) or disabling stroke (mRS > 2) at 10 years. All patients managed according to clinical judgment alone will be included in the registry. The study is registered under: wwwTrials.gov , ID: NCT02098252 . Expected results A minimum recruitment of 540 patients is required to show that treatment can reduce the primary outcome by 10 % (from 25 to 15 %); 440 patients will be needed to show a 10 % increase in angiographic occlusion for a good clinical outcome with pre-embolization. Conclusion The trial is designed to offer optimal and verifiable care to patients with brain AVMs in spite of the uncertainty. We are currently seeking the participation of multiple centers.

BACKGROUND The ascending pharyngeal artery (APA) may, in very rare cases, supply the posterior inferior cerebellar artery (PICA). In reported cases, when such is the case, the ipsilateral vertebral artery (VA) does not supply the PICA, and most of the time it is hypoplastic. OBJECTIVE To describe a unique cadaveric observation of a direct anastomosis between the posterior division (neuromeningeal) of the jugular branch of the APA and the PICA, where the PICA is also supplied by a normal-size VA. METHODS A direct connection between the APA and the PICA was examined in a cadaveric specimen using a 3-dimensional endoscope and a surgical microscope. RESULTS The enlarged jugular branch of the posterior division of the APA entered intracranially via the jugular foramen in its pars vascularis. It then connected directly with the lateral medullary segment of the PICA. The first segment of the PICA originated from a left vertebral artery of normal size and continued its normal course beyond the junction with the jugular branch of the APA. CONCLUSION Both the VA and the jugular branch of the APA may simultaneously supply the PICA territory. Recognition of this anatomic variant is relevant when planning surgical or endovascular treatments.

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.

Objective The surgical repair of a cerebral aneurysm does not always lead to complete occlusion. A standardized repeatable method of reporting results of surgical clipping is desirable. Our purpose was to systematically review methods of classifying aneurysm remnants, provide a new scale with precise definitions of categories, and perform an agreement study to assess the variability in adjudicating remnants after aneurysm clipping. Methods A systematic review was performed to identify ways to report angiographic results of surgical clipping between 1963 and 2017. Postclipping angiographic results of 43 patients were also independently evaluated by 10 raters of various experience and backgrounds using a new 4-category scale. Agreement between responses were analyzed using κ statistics. Results The systematic review yielded 63 articles with 37 different nomenclatures using 2–6 categories. The reliability of judging the presence of an aneurysm remnant on catheter angiography was studied only twice, with only 2 raters each time, with contradictory results. Interobserver agreement using the new 4-category scale was moderate (κ = 0.52; 95% confidence interval, 0.43–0.62) for all observers, but improved to substantial (κ = 0.62; 95% confidence interval, 0.47–0.76) when results were dichotomized (grade 0/1 vs. 2/3). Conclusions Various classification schemes to evaluate angiographic results after surgical clipping exist in the literature, but they lack standardization. Adjudication using fewer, better defined categories may yield more reliable agreement.

Most neurovascular innovations have been introduced by using case series followed by observational studies. A better approach would be a pragmatic randomized trial. Two important aspects of trial design, patient selection and randomized allocation, remain poorly understood. We discuss the role trial methodology can play in the protection of patients being offered innovative treatments.

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.

BACKGROUND AND PURPOSE: Rabbit elastase-induced saccular aneurysms have been commonly used for preclinical testing of endovascular devices, including flow diverters. However, all tested devices have been shown to be capable of aneurysm occlusion with this model. We aimed to create a more challenging model to test and discriminate among neurovascular devices of varying efficacies. MATERIALS AND METHODS: With a surgical approach that included elastase infusion and balloon dilation, we attempted the creation of complex fusiform aneurysms in 16 rabbits, with standard saccular carotid aneurysms created in 15 other animals. Aneurysms were randomly allocated to one of the following treatments: flow diversion (n = 8), high-porosity stent (n = 6), double high-porosity stent (n = 5), and control (n = 6). Angiographic assessment and pathologic analyses were performed at 3 months. RESULTS: Creation of complex fusiform and standard saccular aneurysms was successful in 12/16 and 13/15 attempts, respectively. All saccular (n = 4) or complex fusiform (n = 4) aneurysms treated with flow diverters were successfully occluded. Three of 3 saccular compared with 0/2 complex fusiform aneurysms were occluded by double high-porosity stents. One of 3 saccular and 0/3 complex fusiform aneurysms were occluded by a single high-porosity stent. Both aneurysm types shared the same pathologic findings when untreated: The aneurysm wall lacked an elastic layer and smooth muscle cells, while the lumen was lined with neointima of varying thickness. Neointimal coverage of the devices was complete when aneurysms were occluded, while leaks were always associated with aneurysm remnants. CONCLUSIONS: Challenging fusiform aneurysms can be created in rabbits by using a surgical modification of the elastase method.

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.

Flow diverters (FDs) are increasingly used for complex intracranial aneurysms. As these self-expanding devices are deployed across an aneurysm neck, they can undergo deformations. The potential clinical consequences of FD deformations remain unclear. We describe an immediate thrombotic complication attributed to a stereotypical stenotic deformation of an FD extremity that can occur when landing zones are of insufficient length. This case is supplemented with in vitro studies showing the relationship between i) the length of the landing zones and ii) discrepancies between the diameter of the device and recipient vessel, and the severity of FD stenosis. In vitro, a shorter landing zone was associated with a progressive stenotic deformation of the terminal ends of all FDs studied. This deformation was more pronounced when the diameter of the device was oversized compared to the size of the recipient tube. In our clinical case, the presence of this deformation led to an immediate thrombotic complication, requiring deployment of a second stent to correct the observed stenosis. In addition, treatment failure ultimately led to a fatal rupture, a failure that can be explained by residual flows through a more porous transition zone, another characteristic FD deformation which occurs when they are oversized as compared to the parent vessel, but free to expand at the level of the aneurysm. Proper selection of device diameter and length of the landing zone is important, and may decrease the incidence of deformation-related complications.

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.

OBJECTIVEThe Flow Diversion in the Treatment of Intracranial Aneurysm Trial (FIAT) was designed to guide the clinical use of flow diversion, an innovative method to treat intracranial aneurysms, within a care trial and to study safety and efficacy.METHODSFIAT, conducted in 3 Canadian hospitals, proposed randomized allocation to flow diversion or standard management options (observation, coil embolization, parent vessel occlusion, or clip placement), and a registry of non-randomized patients treated with flow diversion. The primary safety outcome was death or dependency (modified Rankin Scale score > 2) at 3 months, to be determined for all patients who received flow diversion at any time. The primary efficacy outcome was angiographic occlusion at 3–12 months combined with an independent clinical outcome.RESULTSOf 112 participating patients recruited between May 2, 2011, and February 25, 2015, 78 were randomized (39 in each arm), and 34 received flow diversion within the registry. The study was halted due to safety concerns. Twelve (16%) of 75 patients (95% CI 8.9%–26.7%) who were allocated to or received flow diversion at any time were dead (n = 8) or dependent (n = 4) at 3 months or more, crossing a predefined safety boundary. Death or dependency occurred in 5 (13.2%) of 38 patients randomly allocated and treated by flow diversion (95% CI 5.0%–28.9%) and in 5 (12.8%) of 39 patients allocated to standard treatment (95% CI 4.8%–28.2%). Efficacy was below expectations of the trial hypothesis: 16 (42.1%) of 38 patients (95% CI 26.7%–59.1%) randomly allocated to flow diversion failed to reach the primary outcome, as compared with 14 (35.9%) of 39 patients allocated to standard treatment (95% CI 21.7%–52.9%).CONCLUSIONSFlow diversion was not as safe and effective as hypothesized. More randomized trials are needed to determine the role of flow diversion in the management of aneurysms.Clinical trial registration no.: NCT01349582 (clinicaltrials.gov)

Objective Randomized allocation of treatment options is not well accepted within the clinical community. Some methods of implementation may be received more favorably than others. Prerandomization may be an acceptable means to facilitate recruitment in some clinical trials. Methods We first compare randomization and prerandomization using illustrative neurovascular trials. We review some problems with conventional trials, Zelen's prerandomization as an alternative method, and the ethical issues that have surrounded prerandomization since its inception in a historic trial. Conventional and Zelen's randomization are then compared with other means to provide and verify care in the context of clinical uncertainty. Results The major problem with conventional randomization is that consent is requested for 2 management options, one of which the patient will not receive. The problem with prerandomization is that treatment is allocated before the patient has consented to trial participation. Prerandomization may trade recruitment difficulties for excessive crossovers. However, other ways to practice under uncertainty and verify patient outcomes, such as case series and registries, are more ethically and scientifically problematic. Conclusions Until the ethical functions of randomized allocation of selected treatment options in the care of patients are recognized by the neurovascular community, Zelen's prerandomization may help recruitment into difficult trials and contribute a means to provide best possible care in the presence of uncertainty.

Background and purpose A patient with a previously Y-stented giant left middle cerebral artery (MCA) bifurcation aneurysm returned with a recurrence. Materials and methods A flow diverter (FD) was deployed through one limb of the high-porosity Y-stenting construction. The proximal FD failed to expand and an attempt at balloon angioplasty led to fatal rupture of the MCA. Results Autopsy demonstrated subarachnoid hemorrhage, vessel rupture and fracture of the proximal high-porosity stent. Microscopic photographs showed that the FD had failed to open because the guiding wire had inadvertently exited and re-entered the proximal segment of the high-porosity stent partially incorporated to the wall of the MCA. Balloon dilatation of the FD which had remained collapsed between the stent and the vessel wall caused fracture of the stent and rupture of the artery. Conclusion Angioplasty and flow-diversion of previously Y-stented aneurysms can lead to serious complications.

Unruptured intracranial aneurysms (UIAs) are increasingly discovered and preventive interventions increasingly performed; from 2000 to 2010, rates of coiling have exploded (14-fold from 0.3 to 4.3 per 100 000 American Medicare beneficiaries).1 The problem is that no one knows whether preventive interventions do more harm than good. During the same period, rates of subarachnoid hemorrhage (SAH) also increased from 20 to 25 per 100 000.1 Questioning the merit of preventive interventions is long overdue, but once questions are raised, how to properly address them? On the surface, one reasonable answer is to try to identify patients for whom treatment would be indicated and separate them from patients for whom treatment would be futile or harmful. The idea makes sense, provided we proceed with the right methods. The core problem starts when a ‘natural history’ approach is employed. This method had noble beginnings, with the observation of animals and plants by Aristotle and Pliny the Elder,2 ,3 but it has now disappeared from all other domains in medicine, except ours. The most recent product of this approach is the PHASES scoring system, which proposes ‘a risk prediction chart to guide clinical decisions’.4 ,5 A fundamental question is whether this approach is scientific or pseudoscientific. Karl Popper attempted to demarcate science from pseudoscience: ‘A theory which is not refutable by any conceivable event is nonscientific. Irrefutability is not a virtue of a theory (as people often think) but a vice’.6 Let's see whether PHASES was designed to be refutable. Natural history studies have long looked for risk factors for rupture, such as aneurysm …

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 The International Subarachnoid Aneurysm Trial (ISAT) was a major study comparing clipping and coiling of ruptured intracranial aneurysms. The trial provided answers that were the subject of multiple letters and editorial comments. Methods We review the most common critiques that were published in major neurosurgical journals, trying to identify what aspects of ISAT could have been improved, and what questions remain to be studied. Results Frequent critiques include imprecise selection criteria, lack of requirement for the technical proficiency of surgical participants, lack of angiographic controls of surgically treated patients, and poorly chosen primary endpoints. Other issues that are often raised are the poor recruitment rate which endangered generalization of results, the excessive delays in performing clipping which led to rebleeding episodes, lack of blinding in the assessment of outcomes, and subjective questionnaires. Nonetheless, the design of the study as a pragmatic trial was appropriate, as was the choice of the primary endpoint. The overall trial results could not be verified for all subgroups of interest, and currently many patients who would not have been included in ISAT are treated by coiling, while other patients are treated by clipping despite ISAT results. Hence a new trial, complementary to the original ISAT, may now be indicated. Conclusion ISAT was well-designed and conducted, but many questions remain. They should be addressed by a new trial.

Resume Contexte et objectifs L’etude International Subarachnoid Aneurysm Trial (ISAT) sur les anevrismes fut une etude marquante. ISAT effectua une comparaison entre le clipping et le coiling des anevrismes intracrâniens rompus, et fournit des reponses qui furent abondamment commentees dans de multiples lettres et remarques editoriales. Methodes Les critiques les plus frequentes publiees dans les principaux periodiques neurochirurgicaux sont passees en revue. Nous tentons d’identifier les aspects d’ISAT susceptibles d’amelioration et les questions qu’il nous faut encore approfondir. Resultats Les critiques les plus frequentes furent les suivantes : criteres de selection qui manquent de precision, un manque d’exigences concernant la competence technique des chirurgiens participants, l’absence de controles angiographiques pour les patients traites chirurgicalement, et des criteres de jugement des resultats cliniques qui laissent a desirer. D’autres problemes souleves inclurent : un faible taux de recrutement qui compromet la generalisation des resultats, des delais excessifs avant le clipping qui menerent a des episodes de resaignement, le manque d’evaluation en aveugle des resultats cliniques, et des questionnaires subjectifs. Neanmoins, la conception de l’etude en tant qu’essai pragmatique ainsi que le choix du critere principal sont ici juges appropries. Les resultats generaux ne purent cependant etre verifies pour tous les sous-groupes. Presentement, de nombreux patients qui n’auraient pas ete inclus dans ISAT sont traites par coiling, alors que d’autres sont traites par clipping malgre les resultats d’ISAT. Par consequent, un nouvel essai clinique, complementaire a l’ISAT original, serait a present indique. Conclusion ISAT fut bien concu et bien mene, mais plusieurs questions demeurent sans reponses. Elles doivent etre abordees dans un nouvel essai clinique.

Resume Contexte Une fois que la decision de traiter un anevrisme intracrânien est prise, les cliniciens doivent choisir l’une de deux options de traitement : la chirurgie ouverte ou le traitement endovasculaire. La justification sous-jacente au choix de la modalite de traitement demeure obscure. Methode Nous discutons les facteurs cites dans la litterature se rapportant au patient et a l’anevrisme qui influenceraient le choix du traitement. Resultats La pertinence et l’incidence sur le sens de la decision du statut de la rupture, de l’âge, du type de presentation clinique, de l’etat de sante general, ainsi que de la taille, la localisation et la morphologie de l’anevrisme et la multiplicite des lesions sont passees en revue. La validite de ces facteurs dans la prise de decision demeure douteuse, puisque le meme facteur peut donner lieu a des opinions opposees selon la technique du praticien. Les differences percues dans la securite et l’efficacite entre les deux approches sont souvent invoquees pour tenter de justifier les choix de traitement. Nous discutons des difficultes liees a la selection et au raisonnement au cas par cas. Conclusion Il est necessaire de concevoir et d’executer des essais cliniques randomises adequats pour trancher la controverse et determiner la modalite de traitement optimale des anevrismes intracrâniens. Etant donne le manque de connaissances fiables justifiant l’une ou l’autre option de traitement, le choix le plus ethiquement approprie pour les cliniciens de formation chirurgicale ou endovasculaire est de participer a des essais randomises.

Resume Contexte et objectif Certaines questions fondamentales concernant le traitement des anevrismes intracrâniens demeurent toujours controversees. Nous passons en revue ici le role qu’ont joue les essais randomises dans le choix du meilleur traitement des anevrismes intracrâniens dans les premiers temps du clipping neurochirurgical. Methode Nous avons procede a l’analyse des essais cliniques marquants et des grandes etudes cooperatives. Les resultats sont presentes sous forme de synthese narrative. Resultats Les preuves les plus convaincantes en faveur du traitement chirurgical des anevrismes intracrâniens rompus proviennent des premiers essais controles randomises (ECR) menes des annees 1950 aux annees 1970. De grandes etudes observationnelles historiques, effectuees entre les annees 1970 et 2000, visant a guider la pratique clinique, n’ont fourni que des associations statistiques entremelees de facteurs confondants. Suite a ces premiers ECR, un gain substantiel en connaissances fiables ne put avoir lieu qu’avec l’achevement de l’International Subarachnoid Aneurysm Trial (ISAT), 25 ans plus tard. Conclusion Nous devons nous inspirer des neurochirurgiens novateurs des premiers essais cliniques si nous voulons realiser de reels progres dans notre comprehension du meilleur traitement des anevrismes intracrâniens.

Resume Contexte et objectif Le traitement le plus approprie des anevrismes non rompus demeure un sujet de controverse. Une estimation precise de la morbidite et de l’efficacite de chaque type de traitement est une information presumee necessaire pour guider les choix therapeutiques. Methodes On rapporte les resultats de deux revues systematiques de la litterature, des series de cas et des etudes epidemiologiques concernant la morbidite et l’efficacite du clipping chirurgical et du traitement endovasculaire des anevrismes non rompus recemment publiees. Une analyse critique de la qualite methodologique des etudes disponibles et de la fiabilite des resultats est suivie d’une evaluation de la logique de ce type de recherche clinique sur les anevrismes non rompus. Resultats On a trouve chez 692 des 9845 patients des resultats non favorables, incluant la mort, a un an apres le clipping chirurgical (moyenne 6,7 % ; IC a 99 % : 4,9–9,0 %). Des resultats defavorables apres traitement endovasculaire sont survenus chez 4,8 % (189/5044; IC a 99 % : 3,9–6,0 %). La localisation et la taille des anevrismes constituaient des facteurs de risque d’une evolution defavorable en cas de clipping, alors qu’aucun facteur de risque n’a atteint le seuil statistique significatif en cas d’embolisation. La qualite methodologique des etudes incluses etait faible en general. Les estimations des etudes epidemiologiques montraient des taux de morbidite plus eleves que les revues de series de cas. L’efficacite a long terme n’a pu etre evaluee sur les donnees de la litterature pour aucun des deux traitements. Toutes ces etudes tentent de repondre a des questions jamais proprement posees. Conclusion Les resultats des revues systematiques et des etudes observationnelles ne devraient servir qu’a l’elaboration d’hypotheses pour des essais cliniques controles.