Daniel Roy

Endovascular Treatment of Intracranial Unruptured Aneurysms: Systematic Review and Meta-Analysis of the Literature on Safety and Efficacy

PURPOSE To report an updated, systematic review of medical literature from January 2003 to July 2008, on endovascular treatment (EVT) of intracranial unruptured aneurysms (UAs) (a) to assess the morbidity and case fatality rate of EVT of UAs, (b) to understand how bias can affect results, and (c) to estimate the efficacy of EVT by using reported digital subtraction angiographic (DSA) results and clinical follow-up events. MATERIALS AND METHODS This article was prepared in accordance with the Meta-Analysis of Observational Studies in Epidemiology and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The literature was searched by using PubMed and the EMBASE and Cochrane Library databases. Eligibility criteria were (a) explicit procedural mortality and morbidity rates; (b) at least 10 patients; (c) saccular, intradural, nondissecting UAs; (d) original study published in English or French between January 2003 and July 2008; and (e) a methodological quality score higher than 6, according to Strengthening the Reporting of Observational Studies in Epidemiology criteria. End points included procedural mortality and morbidity, defined as a modified Rankin scale score of 3-6 at 1 month, and efficacy, estimated by using immediate and follow-up digital subtraction angiographic results, as well as delayed hemorrhagic events. RESULTS Seventy-one studies were included. Procedural unfavorable outcome was found in 4.8% (random-effect weighted average; 189 of 5044) of patients (99% confidence interval [CI]: 3.9%, 6.0%). Immediate angiographic results showed satisfactory occlusion in 86.1% (2660 of 3089) of UAs. Recurrences were shown in 321 (24.4%) of 1316 patients followed up for 0.4-3.2 years. Retreatment was performed in 9.1% (random-effect weighted average; 166 of 1699) of patients (99% CI: 6.2%, 13.1%). The annual risk of bleeding after EVT was 0.2% (random-effect weighted average; nine of 1395) of patients (99% CI: 0.1%, 0.3%), but clinical follow-up was short, limited to the first 6 months for 76.7% (n = 1071) of reported patients. CONCLUSION EVT of UAs can be performed with relative safety. The efficacy of treatment as compared with observation has not been rigorously documented.

Association of endovascular therapy of very small ruptured aneurysms with higher rates of procedure-related rupture

OBJECT Procedure-related rupture during endovascular therapy of intracranial aneurysms is associated with a mortality rate of more than one third. Previously ruptured aneurysms are a known risk factor for procedure-related rupture. The objective of this study was to evaluate whether very small, ruptured aneurysms are associated with more frequent intraprocedural ruptures. METHODS This was a retrospective cohort study in which the investigators examined consecutive ruptured aneurysms treated with coil embolization at a single institution. The study was approved by the institutional review board. Very small aneurysms were defined as < or = 3 mm. Procedure-related rupture was defined as contrast extravasation during treatment. Univariate analysis with the Fisher exact test and the Mann-Whitney U test was performed. RESULTS Between August 1992 and January 2007, 682 aneurysms were selectively treated with coils in 668 patients. Procedure-related rupture occurred in 7 (11.7%) of 60 aneurysms < or = 3 mm, compared with 14 (2.3%) of 622 aneurysms > 3 mm (relative risk 5.2, 95% confidence interval 2.2-12.8; p < 0.001). Among cases with procedure-related rupture, inflation of a compliant balloon was associated with better outcome (Glasgow Outcome Scale Score > or = 4) compared with patients treated without balloon assistance (5 of 5 compared with 7 of 16; p = 0.05). Death resulting from procedure-related rupture occurred in 8 (38%) of 21 patients, and a vegetative state occurred in 1 patient. Clinical outcome was good in the other 12 patients (57%). CONCLUSIONS Endovascular coil embolization of very small (< or = 3 mm) ruptured cerebral aneurysms is 5 times more likely to result in procedure-related rupture compared with larger aneurysms. Balloon inflation for hemostasis may be associated with better outcome in the event of intraprocedural rupture and merits further study.

Fibrinogen and Vascular Smooth Muscle Cell Grafts Promote Healing of Experimental Aneurysms Treated by Embolization

BACKGROUND AND PURPOSE Residual necks and recurrences frequently occur after endovascular treatment of cerebral aneurysms. Addition of fibrinogen and vascular smooth muscle cells (VSMCs) to the embolic material may promote healing of embolized aneurysms by increasing neointima formation at the neck. METHODS Bilateral carotid aneurysms were constructed with venous pouches in 31 dogs. Aneurysms were packed intraoperatively with bare Gelfoam sponges, sponges treated with fibrinogen, or fibrinogen sponges seeded with the animals own VSMCs or peripheral blood mononuclear cells. Animals were killed after angiography at 3 weeks, and morphometric studies were performed to measure the thickness of the neointima at the neck of treated lesions. Angiographic results and mean thickness of neointimas were compared using ANOVA. In 8 animals, 1 aneurysm was embolized with sponge seeded with VSMCs transduced by adenoviral infection to express a fluorescent protein (green fluorescent protein), and gene expression was monitored for 4, 7, 14, and 21 days by fluorescent microscopy. RESULTS Aneurysms treated with sponges seeded with VSMCs had significantly thicker neointimas and were more completely obliterated at 3 weeks than control aneurysms treated with fibrinogen sponges. Peripheral blood mononuclear cells could not reproduce these findings. Sponges treated with fibrinogen alone promoted formation of a thicker neointima than bare sponges. Transduced cells transplanted into in vivo aneurysms still expressed green fluorescent protein at 3 weeks. CONCLUSIONS VMSC grafts can improve healing of experimental aneurysms treated by embolization. Transplantation of cells transduced to express a foreign gene opens the way for in situ gene therapy for cerebral aneurysms.

Endovascular treatment of pericallosal aneurysms.

OBJECT Pericallosal artery aneurysms are uncommon. Their treatment strategy, surgical or endovascular, will present specific challenges. The objective of the study was to compare risks of coil therapy and the recurrence rate of pericallosal artery aneurysms with aneurysms in other intradural locations. METHODS The authors examined data that were stored in a prospectively collected database for pericallosal artery aneurysms in patients who underwent coil placement between 1992 and 2005. Hemorrhagic and thromboembolic complications as well as clinical and angiographic outcomes were reviewed. Angiographically documented recurrences were classified as minor or major. These lesions were compared with a historical cohort of non-pericallosal artery aneurysms in patients who underwent coil therapy between 1992 and 2002. The known risk factors for recurrence and procedure-related hemorrhagic complications were evaluated in both groups to assess baseline imbalances. RESULTS During a 13-year period, 25 pericallosal artery aneurysms were treated with coils in 25 patients. The non-pericallosal artery lesion group included 488 aneurysms of which 344 underwent follow-up imaging. Procedure-related perforations were more frequent for pericallosal artery aneurysms than those in other intradural locations (three of 25 compared with eight of 476, respectively; risk ratio 7.1, 95% confidence interval [CI] 2.1-22.5, p = 0.03). Follow-up imaging studies (obtained at a mean 28 months) were available for 19 patients with pericallosal artery aneurysms. The recurrence rate was not significantly higher in these patients (22.9/100 person-years of observation) than in those with non-pericallosal artery aneurysms (17.9/100 person-years of observation) (incidence rate ratio 1.3, 95% CI 0.6-2.4, p = 0.46). CONCLUSIONS Pericallosal artery aneurysms were associated with significantly higher periprocedural rupture than non-pericallosal artery lesions. No significant intergroup difference was found for aneurysm recurrence.

Chimeric fibronectin matrix mimetic as a functional growth- and migration-promoting adhesive substrate.

Therapeutic protein engineering combines genetic, biochemical, and functional information to improve existing proteins or invent new protein technologies. Using these principles, we developed an approach to deliver extracellular matrix (ECM) fibronectin-specific signals to cells. Fibronectin matrix assembly is a cell-dependent process that converts the inactive, soluble form of fibronectin into biologically-active ECM fibrils. ECM fibronectin stimulates cell functions required for normal tissue regeneration, including cell growth, spreading, migration, and collagen reorganization. We have developed recombinant fibronectin fragments that mimic the effects of ECM fibronectin on cell function by coupling the cryptic heparin-binding fragment of fibronectins first type III repeat (FNIII1H) to the integrin-binding domain (FNIII8-10). GST/III1H,8-10 supports cell adhesion and spreading and stimulates cell proliferation to a greater extent than plasma fibronectin. Deletion and site-specific mutant constructs were generated to identify the active regions in GST/III1H,8-10 and reduce construct size. A chimeric construct in which the integrin-binding, RGDS loop was inserted into the analogous site in FNIII8 (GST/III1H,8(RGD)), supported cell adhesion and migration, and enhanced cell proliferation and collagen gel contraction. GST/III1H,8(RGD) was expressed in bacteria and purified from soluble lysate fractions by affinity chromatography. Fibronectin matrix assembly is normally up-regulated in response to tissue injury. Decreased levels of ECM fibronectin are associated with non-healing wounds. Engineering fibronectin matrix mimetics that bypass the need for cell-dependent fibronectin matrix assembly in chronic wounds is a novel approach to stimulating cellular activities critical for tissue repair.

Early CT changes in patients admitted for thrombectomy Intrarater and interrater agreement

Objective: To systematically review the literature and assess agreement on the Alberta Stroke Program Early CT Score (ASPECTS) among clinicians involved in the management of thrombectomy candidates. Methods: Studies assessing agreement using ASPECTS published from 2000 to 2015 were reviewed. Fifteen raters reviewed and scored the anonymized CT scans of 30 patients recruited in a local thrombectomy trial during 2 independent sessions, in order to study intrarater and interrater agreement. Agreement was measured using intraclass correlation coefficients (ICCs) and Fleiss kappa statistics for ASPECTS and dichotomized ASPECTS at various cutoff values. Results: The review yielded 30 articles reporting 40 measures of agreement. Populations, methods, analyses, and results were heterogeneous (slight to excellent agreement), precluding a meta-analysis. When analyzed as a categorical variable, intrarater agreement was slight to moderate (κ = 0.042–0.469); it reached a substantial level (κ > 0.6) in 11/15 raters when the score was dichotomized (0–5 vs 6–10). The interrater ICCs varied between 0.672 and 0.811, but agreement was slight to moderate (κ = 0.129–0.315). Even in the best of cases, when ASPECTS was dichotomized as 0–5 vs 6–10, interrater agreement did not reach a substantial level (κ = 0.561), which translates into at least 5 of 15 raters not giving the same dichotomized verdict in 15% of patients. Conclusions: In patients considered for thrombectomy, there may be insufficient agreement between clinicians for ASPECTS to be reliably used as a criterion for treatment decisions.

Opposing effects of collagen I and vitronectin on fibronectin fibril structure and function.

Extracellular matrix fibronectin fibrils serve as passive structural supports for the organization of cells into tissues, yet can also actively stimulate a variety of cell and tissue functions, including cell proliferation. Factors that control and coordinate the functional activities of fibronectin fibrils are not known. Here, we compared effects of cell adhesion to vitronectin versus type I collagen on the assembly of and response to, extracellular matrix fibronectin fibrils. The amount of insoluble fibronectin matrix fibrils assembled by fibronectin-null mouse embryonic fibroblasts adherent to collagen- or vitronectin-coated substrates was not significantly different 20 h after fibronectin addition. However, the fibronectin matrix produced by vitronectin-adherent cells was ~10-fold less effective at enhancing cell proliferation than that of collagen-adherent cells. Increasing insoluble fibronectin levels with the fibronectin fragment, anastellin did not increase cell proliferation. Rather, native fibronectin fibrils polymerized by collagen- and vitronectin-adherent cells exhibited conformational differences in the growth-promoting, III-1 region of fibronectin, with collagen-adherent cells producing fibronectin fibrils in a more extended conformation. Fibronectin matrix assembly on either substrate was mediated by α5β1 integrins. However, on vitronectin-adherent cells, α5β1 integrins functioned in a lower activation state, characterized by reduced 9EG7 binding and decreased talin association. The inhibitory effect of vitronectin on fibronectin-mediated cell proliferation was localized to the cell-binding domain, but was not a general property of αvβ3 integrin-binding substrates. These data suggest that adhesion to vitronectin allows for the uncoupling of fibronectin fibril formation from downstream signaling events by reducing α5β1 integrin activation and fibronectin fibril extension.

Arterial Onyx embolisation of intracranial DAVFs with cortical venous drainage.

PURPOSE To present our experience with the endovascular management of intracranial dural arteriovenous fistulas with direct cortical venous drainage by trans-arterial embolisation using Onyx. MATERIALS & METHODS Between January 2004 and April 2008, 12 consecutive high grade intracranial dural arteriovenous fistulas (Cognard type III (eight patients) or IV (three patients)) were treated by trans-arterial embolisation with Onyx. The majority of cases were treated by Onyx embolisation alone. One case had additional embolisation with n-butyl-2-cyanoacrylate at the same session. Imaging follow-up was obtained in all but one patient (mean 3.6 months). RESULTS Nine patients had a technical success at the end of the embolisation procedure with complete angiographic exclusion of the fistula. Two patients had a small residual fistula at the end of embolisation, one of which had residual mild cortical venous drainage. Both were stable at follow-up angiography. One patient had a residual fistula supplied by the ophthalmic artery, which was thought to be unsafe to embolise and was sent for surgery, which was curative. In one patient the microcatheter ruptured, with a fragment of the distal microcatheter left in the occipital artery. No clinical complications were observed in this series at clinical follow-up (mean 3.3 months). Two patients were noted to have significant radiation dose. CONCLUSION Endovascular management of intracranial dural arteriovenous fistulas with direct venous cortical drainage by trans-arterial Onyx embolisation is a safe and effective treatment according to our experience. Fluoroscopy times and radiation dose may be a concern.

Endovascular treatment of hemifacial spasm associated with a cerebral arteriovenous malformation using transvenous embolization: case report.

OBJECTIVE AND IMPORTANCE To illustrate that decompression of the facial nerve by transvenous endovascular treatment may relieve hemifacial spasm (HFS) caused by dilated veins. CLINICAL PRESENTATION A 35-year-old man suffered severe chronic right HFS associated with a dilated right lateral mesencephalic vein lying in the vicinity of the facial nerve. This nonessential vein was recruited as a secondary collateral drainage from an inoperable left temporo-occipital arteriovenous malformation. INTERVENTION The lateral mesencephalic vein was reached through the superior petrosal sinus using a transfemoral venous approach and was occluded with interlocking detachable coils (Target Therapeutics, Freemont, CA). There was complete remission of HFS without recurrence after 2.5 years of follow-up. CONCLUSION This case report supports vascular compression in the pathogenesis of HFS and suggests that facial nerve injury is not essential for the therapeutic effect of surgical decompression.

Flow diversion in the treatment of aneurysms: a randomized care trial and registry

OBJECTIVE The 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. METHODS FIAT, 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. RESULTS Of 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%). CONCLUSIONS Flow 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).