Advances in Endovascular Approaches to Cerebral Aneurysms
Dumont, Travis M. MD*,‡; Eller, Jorge L. MD*,‡; Mokin, Maxim MD, PhD*,‡; Sorkin, Grant C. MD*,‡; Levy, Elad I. MD, MBA*,‡,§,¶
Section Editor(s): Bendok, Bernard R. MD; Levy, Elad I. MD
*Department of Neurosurgery, and
§Department of Radiology, School of Medicine and Biomedical Sciences, and
¶Toshiba Stroke and Vascular Research Center, University at Buffalo, State University of New York;
‡Department of Neurosurgery, Gates Vascular Institute, Kaleida Health, Buffalo, New York, NY
Correspondence: Elad I. Levy, MD, MBA, FACS, FAHA, University at Buffalo Neurosurgery, 100 High St, Ste B4, Buffalo, NY 14203. E-mail: email@example.com
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.neurosurgery-online.com).
Received June 03, 2013
Accepted October 11, 2013
Recent advancements in all phases of endovascular aneurysm treatment, including medical therapy, diagnostics, devices, and implants, abound. Advancements in endovascular technologies and techniques have enabled treatment of a wide variety of intracranial aneurysms. In this article, technical advances in endovascular treatment of cerebral aneurysms are discussed, with an effort to incorporate a clinically relevant perspective. Advancements in diagnostic tools, medical therapy, and implants are reviewed and discussed.
ABBREVIATIONS: AMERICA, Axium MicroFX for Endovascular Repair of IntraCranial Aneurysm
CCT, Cerecyte Coil Trial
DSA, digital subtraction angiography
FDA, Food and Drug Administration
HELPS, HydroCoil Endovascular Aneurysm Occlusion and Packing Study
LVIS, Low-Profile Visualized Intraluminal Support
MAPS, Matrix and Platinum Science
PITA, Pipeline Embolization Device for the Intracranial Treatment of Aneurysms
PUFS, Pipeline for Uncoilable or Failed Aneurysms
SAH, subarachnoid hemorrhage
SENAT, Safety and Efficacy of Neuroform for Treatment of Intracranial Aneurysms
Treatment is frequently advised for patients with cerebral aneurysms to eliminate rupture or rerupture risk, with treatment options including open surgical clip ligation and endovascular embolization. Determining the best treatment option for any given aneurysm depends on a host of factors, the most relevant of which are likely to include aneurysm shape and location, as well as the operating surgeon's experience and expertise. Overall, a trend toward increased use of endovascular means to eliminate an aneurysm is evident.1 This has been fueled by advances in endovascular approaches to the treatment of cerebral aneurysms. Such advances have been rendered possible by new technologies that offer treatment options for a wider variety of aneurysms, although complications remain problematic. This review discusses endovascular treatment and follow-up evaluation of aneurysms and emphasizes the role of technological developments that have enabled advances in endovascular approaches to the treatment of cerebral aneurysms.
Simply stated, the devices currently available for cerebral aneurysm embolization are far superior to those available when Guglielmi detachable coil (Boston Scientific, Natick, Massachusetts) embolization was first performed > 20 years ago.2 This includes multiple generations of advancements in imaging technology, detachable coils, delivery catheters, and other devices such as stents, which were not initially available or used for aneurysm treatment. One may foresee similar improvements in technologies or new technologies that improve on or supplant contemporary devices in the near future. Recent advancements in all phases of treatment, including medical therapy, diagnostics, devices, and implants, abound. In this review, technical advances in endovascular treatment of cerebral aneurysms are discussed, with an effort to incorporate a clinically relevant perspective. The clinical perspective is germane because technological advancements may not always lead to improved clinical outcomes and are frequently associated with new complications. We focus on advancements in visualization tools and delivery devices before discussing implants.
ADVANCES IN DIGITAL SUBTRACTION ANGIOGRAPHY
Digital subtraction angiography (DSA), the main imaging modality, is considered the gold standard or benchmark for diagnosing and evaluating aneurysms. Modern developments in DSA allow improved visualization and understanding of aneurysm morphology and serve as important adjuncts during endovascular treatment of intracranial aneurysms.
Three-Dimensional Imaging Technique
Three-dimensional (3-D) DSA allows excellent visualization of aneurysm anatomy and the relationship of the aneurysm with its parent and branching vessels, as well as the selection of optimal working views.3 It is also superior in detecting very small aneurysms that can be missed with conventional DSA, which provides only 2-dimensional projections of the intracranial vasculature. For example, a study of 350 patients with intracranial aneurysms showed superiority of 3-D DSA in diagnosing additional aneurysms, especially those of small (< 3 mm in diameter) size.4
However, caution is advised when interpreting aneurysm anatomy with 3-D DSA images. 3-D DSA might underestimate dome-to-neck aneurysm ratio, which, in turn, can have an influence on an endovascular approach such as use of stent-coil or flow-diversion technique instead of primary coiling (preferable in cases with high dome-to-neck aneurysm ratio).5,6 Therefore, careful examination of both 3-D and conventional 2-dimensional DSA images is critical for accurate determination of aneurysm morphology.
Three-Dimensional Roadmapping Technology
Another tool in the neurointerventionist's arsenal, 3-D roadmapping, allows superimposition of a live fluoroscopic image over a previously obtained 3-D image. If needed, 3-D image software will automatically track and follow changes in the C-arm position, allowing adjustment of the 3-D roadmap axis to match the new live image projections. This technology may reduce procedure time and amount of contrast medium used by assisting the operator with catheterization of aneurysms with complex or tortuous anatomy of the parent vessels.7,8
Flat-Panel Detector Technology
One limitation of DSA is poor visibility of stent struts, which can make it difficult for the operator to assess the exact apposition of the stent to the arterial wall and aneurysm neck in cases of stent-assisted aneurysm coiling or with the use of flow-diversion stents (discussed below). Flat-panel detector angiographic computed tomography (CT) imaging more accurately demonstrates exact stent position, providing critical information during complex stent-assisted coiling procedures such as detection of coil protrusion, stent strut herniation into the aneurysm lumen, and suboptimal coverage of the aneurysm neck by stent struts.9-11 A flat-panel detector can also be used during procedures requiring the use of multiple overlapping stents such as flow-diverting stents; it can identify kinking or twisting of the stents, extent of overlapping segments, or incomplete deployment12 (Figure 1). Flat-panel detector technology works by obtaining multiple images during a single rotation of the angiographic C arm and then reconstructing those images into a 3-D view. Evaluation of aneurysms > 10 mm in diameter can be limited by beam-hardening artifact produced by the coil mass, impairing visualization of the stent.11
Flat-panel detector technology can also be used intraoperatively when a potential complication of aneurysm coiling such as wire perforation and intracranial hemorrhage is suspected.13 Although inferior in quality to conventional noncontrast CT imaging, it can reliably detect intraparenchymal or subarachnoid hemorrhage (SAH) without the need to transfer the patient from the angiography suite.14
Microangiographic Fluoroscopy Technique
This technique uses ultrahigh x-ray resolution within a small field of view, allowing visualization of fine anatomic and procedural details such as the operator's positioning of the microcatheter tip within the coil mass and presence of coil herniation and residual filling after coiling.15,16 It can be used in complex cases such as coiling of very small or irregularly shaped aneurysms with multiple small pockets and treatment of partially thrombosed aneurysms or when encountering difficulty with positioning of the microcatheter.
ADVANCEMENTS IN CATHETERS AND WIRES
Several technological advancements in catheters and microwires aimed at improving access for cerebrovascular procedures have been introduced during the last 10 years. These include guide catheters designed for use in cranial vessels,17-19 soft-tipped microcatheters delivered with soft-tipped, steerable, and easily visualized microguidewires. In our experience, the most notable recent additions to the neuroendovascular toolbox are truly steerable microwires with nearly 1:1 torquing capability (first available in 200620) and catheters with flexible tips designed for navigating tortuous cerebral vasculature19,21 (first available in 200822). In our experience, these devices, in addition to soft-tipped microcatheters, enable safer catheterization of aneurysms, thereby minimizing risk of perforation and iatrogenic SAH. It is somewhat surprising that there has been no appreciable decline in reported perioperative thromboembolic complications or iatrogenic aneurysm perforation between the earliest and most recent prospective studies of aneurysm coiling. Perioperative complications in the first large, prospective, multicenter study (enrollment between 1990 and 1995) included thromboembolic complications in 5.5% and iatrogenic aneurysm perforation in 2.7% of 403 patients.23 This reported complication incidence is similar to that reported (thromboembolic complications in 2.9%-4.7% and iatrogenic aneurysm perforation in 4.3%-5.6%) in recently completed trials (enrollment between 2005 and 2010) comparing different detachable coils.24,25 That improved wires and catheters have not had a measurable impact on the reduction of iatrogenic complications is likely a reflection of more complex aneurysms (and use of adjunctive tools for neck remodeling, discussed below) treated at present than in the initial Guglielmi detachable coil cohort.
ADVANCEMENTS IN DETACHABLE COILS
Many different detachable coils are now available for use in the treatment of cerebral aneurysms. All coils have a similar design; however, subtle differences in most coils are present and warrant discussion. Biologically inert, complex-shaped, and stretch-resistant coils are important components of coil design that have been present in all but the earliest available coils.26 All coils designed for intracranial use have primary, secondary, and tertiary structures (Figure 2). The primary structure is a very thin platinum alloy filament that is wound into a coil or a spring (the secondary structure). The tertiary structure is seen when the coil is removed from its delivery system (typically a helix, sphere, or other complex shape). Because coil “stiffness” felt by the surgeon is experienced as a coil is delivered in its secondary shape (a coil or spring) through a catheter, the “stiffness” of the coil is approximated by considering the following equation for the spring constant of a particular coil:
where D1 is the primary shape, G is the modulus of rigidity of the platinum alloy used to make the coil, D2 is the secondary shape, and n is the number of times the material is wound per unit of distance.1 Because bare coils are made of similar platinum alloys and the number of wraps per unit difference is similar between coils, “stiffness” can be approximated with the following equation:
or coil “stiffness” is directly proportional to the fourth power of the diameter of the primary shape and inversely proportional to the third power of the diameter of the secondary shape. Stated more simply, a smaller D1 or larger D2 translates to “softer” coils.26 This relationship was incorporated into the design of many newer-generation coils, so newer coils are more easily delivered than earlier-generation coils. For example, coils are now available with D1 of 0.00125 in, which is a considerably thinner wire than the earliest coils, which had a D1 of 0.00300 in. Coils are currently produced with variable D2 between 0.01 and 0.02 in, which results in variable “stiffness” between different coils.
Coils with larger D2 have a theoretical increase in packing density compared with coils with a smaller D2 but similar D1 and length. An extreme example of this is the P400 coil system (Penumbra, Inc, Alameda, California; Figure 3). These coils have a D2 of 0.0020 in, the largest currently available for use in the treatment of cerebral aneurysms. Within the P400 coil, a second, smaller nitinol coil provides structural support (Figure 3) but makes comparison of stiffness with other coils (which typically have no inner structure beyond a stretch-resistant filament) difficult. Retrospective in vivo studies have reported that an increased packing density may be achieved with P400 coils compared with complex coils with smaller D2.27,28 Further study is required to determine whether this translates to diminished recanalization rates associated with the use of these coils compared with smaller complex coils. In our experience, these coils are more difficult to deliver than other coils. We have therefore limited their use to large and giant aneurysms.
In vitro29 and in vivo30 studies have reported that complex coils increase aneurysm packing densities compared with helical coils. The reason is the ability of complex coils to take the shape of the outer wall of the aneurysm, which allows an out-to-in filling of the aneurysm with sequentially smaller complex coils. The outermost coil is sized to fit the outer diameter of the aneurysm. In part as a result of improved packing density, complex coils may have a reduced rate of recanalization compared with helical coils.31 For treatment of aneurysms, we now generally use helical coils for increasing packing density after placement of spherical or complex-shaped coils.
Although most coils are composed of biologically inert bare platinum alloy, several coils have been developed that are coated with a bioactive substance (eg, a layer of hydrophilic acrylic polymer) that expands when exposed to aqueous solution (ie, blood) and can triple the dry volume of the coil.32 Such coils have a theoretical benefit in that their size when delivered is comparable to that of a bare platinum coil, but their packing density is greater after delivery compared with bare platinum coils, which may then limit recanalization in a manner superior to bare platinum coils. Three randomized trials have been performed to compare bioactive coils with bare platinum coils, none of which displayed any superiority of bioactive coils over bare platinum coils with respect to aneurysm occlusion.24,33-35 The primary outcome and follow-up timing for each trial were well defined but unique to each study, making comparison between studies difficult. However, there was no significant difference in the primary outcome for each of the 3 trials, although noninferiority of each bioactive coil to bare platinum coils was confirmed in each trial. Clinically relevant perioperative complications were no different between treatment groups in all trials.24,33,35 Clinically relevant rehemorrhage rates were infrequent (8 total among 1625 composite patients in the 3 trials), with most (6 of 8) occurring in patients with recent SAH and no difference between coil types. The retreatment rate for active coils compared with bare coils was similar in all 3 randomized trials: 2.5% and 3.6% for hydrogel and bare platinum coils, respectively, in the HydroCoil Endovascular Aneurysm Occlusion and Packing Study (HELPS),36 7.7% and 3.5% for Cerecyte (Codman, Raynham, Massachusetts) and bare platinum coils, respectively, in the Cerecyte Coil Trial (CCT),24,34 and 13.3% and 14.6% for Matrix (Stryker Neurovascular, Fremont, California) and bare platinum coils, respectively, in the Matrix and Platinum Science (MAPS) trial33 (the retreatment end point in MAPS was a composite end point including rerupture and death). There was a trend toward greatest benefit for bioactive coils in aneurysms measuring between 5 and 10 mm in HELPS36 and in aneurysms with complete treatment at completion of the index procedure in MAPS,33 although further study is required to determine the superiority of bioactive coils compared with bare platinum coils in these scenarios.
Fibered coils represent another class of “active” coils (such as the Axium MicroFX, Covidien, Irvine, California). These coils are designed with nylon strands built into the secondary structure of the coil (Figure 4). Once deployed, the nylon strands create a lattice of material in addition to the tertiary structure of the platinum coil. An in vitro fluid dynamics study has shown a reduction of flow into an aneurysm treated with fibered coils compared with bare coils,37 which in theory may favor early hemostasis. This concept remains relatively untested, although the safety of these coils has been displayed in a small prospective registry, with acceptable aneurysm obliteration rates.38 A larger, prospective, single-arm study including 100 patients treated with fibered coils has completed enrollment (Axium MicroFX for Endovascular Repair of IntraCranial Aneurysm [AMERICA]), with a report of outcomes yet to be released.39 We have found these coils to be more difficult to deliver compared with similarly sized bare platinum coils.
In a discussion of advances in detachable coil design, the importance of advancements in coil detachment should not be overlooked. Mechanical or electrolytic detachment mechanisms present in each coil system are all somewhat different and proprietary. For the currently available coil systems, a coil typically requires a few seconds (for mechanical detachment systems) to minutes (for electrolytic systems) to detach, which is clearly an improvement over the original Guglielmi detachable coils, which reportedly required 4 to 12 minutes to detach40 but often required significantly more time for detachment. Better detachment systems therefore equate directly to quicker procedures,41 and advances in these systems have had a dramatic impact on decreasing the duration of an aneurysm coiling procedure.
ADVANCES IN LIQUID EMBOLICS
Liquid embolic agents provide an alternative to coils for aneurysm obliteration. Theoretically, a liquid embolic agent would provide complete packing of an aneurysm, which would be an improvement compared with coil embolization. The best-studied liquid embolic agent used for embolization of cerebral aneurysms is an ethylene-vinyl alcohol copolymer (Onyx HD500, Covidien) dissolved in dimethyl sulfoxide. The concentration of ethylene-vinyl alcohol in Onyx HD500 is 20%, significantly greater than that of the Onyx formulations used to treat cerebral vascular malformations (Onyx 18, 6%; Onyx 34, 8%).42 When used for aneurysm treatment, this embolic agent is delivered into the aneurysm fundus though a microcatheter jailed into position within the aneurysm dome with a conformable balloon inflated within the parent vessel. Ideally, Onyx HD500 is then infused within the aneurysm dome, resulting in immediate aneurysm obliteration. Vessel wall reconstruction may occur, with neointima forming at the site of the aneurysm neck. A prospective registry of 97 patients with 100 aneurysms showed efficacy in aneurysm embolization (complete occlusion in 64%); however, neurological complications occurred in 16 patients (17%).43 Furthermore, delayed occlusion of the parent vessel (thought in many cases to be related at least in part to inadequate antiplatelet medication) was reported in 9 patients. Retrospective series consisting of 21 to 100 cases report aneurysm obliteration rates on the order of 65% to 90%, with a 3% to 45% incidence of neurological complications (summated mean ± SD, 14 ± 14% in 306 patients).44-49 Delayed parent vessel occlusion or stenosis was reported in 0 to 18% of cases (summated mean ± SD, 4.9 ± 5.8% in 306 patients). Problems with delayed vessel occlusions have not abated with routine use of dual antiplatelet medication, according to a recent series.50
Although use of Onyx HD500 is typically reserved for difficult cases, including wide-necked aneurysms and previously treated aneurysms, neurological complications and parent vessel occlusion occur at higher rates with Onyx embolization than with other means of endovascular treatment. At present, we do not view liquid embolic embolization as the ideal solution for any aneurysm, with the exception of distal aneurysms in the setting of negative provocative testing.51 We feel, in practice, the risk of liquid embolic embolization is too great a risk, with superior treatment options available in most cases.
ADVANCES IN ANEURYSM NECK RECONSTRUCTION DEVICES
Before the introduction of stents and balloons, only aneurysms with favorable dome-to-neck ratios could be safely treated through endovascular approaches (ie, with Guglielmi detachable coils).23,52,53 The use of compliant balloons for temporary aneurysm neck remodeling was first reported in 199454 and continues nearly 20 years later without dramatic change in technique or balloon catheter design (excepting for improved navigability of balloon catheters designed for intracranial use). However, many wide-necked aneurysms are not amenable to temporary neck reconstruction and require implanted devices within the parent vessel for adequate endovascular aneurysm obliteration. In recent prospective coiling studies that permitted stent assistance, stents were used in roughly one-fourth to one-fifth of the cases.33,35 The principal risks of intracranial stent placement are vessel perforation with delivery or attempted delivery and thromboembolic events during or after placement of the stent. Dual antiplatelet medications are administered to patients undergoing intracranial stenting to limit thromboembolic events. Generally, these medicines are continued for at least 3 months after placement of an intracranial stent. A better understanding of the importance of prolonged antiplatelet medication after placement of intracranial stents may limit the incidence of delayed thromboembolic complications that was noted in early reports, particularly with the Enterprise stent (Codman).55
The antiplatelet medication used in conjunction with intracranial stent implantation exposes patients to hemorrhagic risks, an issue that becomes particularly important in the setting of recent neurosurgical procedures.56 Although we do not recognize acute SAH as a contraindication for stent reconstruction, the incidence of perioperative complications in this setting is likely greater with stenting than without.56,57
Thin-Film Nitinol Hypotube Stents
The focus of the discussion in this subsection is on Food and Drug Administration (FDA)--approved stents, although it is worth noting that several other stents designed for intracranial use are available outside the United States. Two stent devices have been approved by the FDA for use under the humanitarian device exemption program. They include the open-cell Neuroform stent (Stryker Neurovascular) and the closed-cell Enterprise stent. Both stents are self-expanding stents laser-cut from thin film nitinol hypotubes with little outward radial force that were designed for intracranial use in the treatment of cerebral aneurysms.58
The Neuroform stent, first introduced in 2001, is an open-cell stent available in multiple nominal diameters (between 2.5 and 4.5 mm) and lengths (between 10 and 20 mm). It contains 6 to 8 radiolucent linked cells, with radiopaque platinum markers at either end. This stent has undergone considerable changes in structure and delivery mechanism since its introduction.59,60 Earlier generations of the stent required use of a 3F microcatheter with a 2F stabilizer that was often difficult to deliver because of the unacceptable friction created within the system. This resulted in several early reports of difficulty in navigation or delivery.61-65 The NeuroformEZ is the newest generation of the Neuroform stent (first available in 2010); it has a more streamlined delivery system (delivered through any 0.027-in inner diameter microcatheter) and is more navigable than earlier designs (Figure 5).66 A recent prospective study of wide-necked aneurysms treated with the Neuroform stent conducted in France between January 2008 and April 2010 (Safety and Efficacy of Neuroform for Treatment of Intracranial Aneurysms [SENAT]) displayed high rates of aneurysm occlusion with low rates of retreatment.67 In this study, 107 patients with 107 wide-necked aneurysms were treated with detachable coils in conjunction with the Neuroform stent. Complete aneurysm occlusion was obtained in 66% of patients after the procedure. Perioperative thromboembolism was noted in 4%, with an additional incidence of delayed thromboembolic events in 3%. Mortality and permanent morbidity at 12 to 18 months of follow-up evaluation were reported in 1% of patients. Aneurysm recurrence was reported in 10%, with 4% undergoing retreatment. Two other prospective studies displayed safety of the Neuroform stent60,63 but are too small to make generalizations about obliteration rates or thromboembolic events. Several retrospective studies of patients treated with the Neuroform stent (including between 41 and 284 patients) have displayed efficacy of obliteration (48%-96%61,68-72), with low perioperative mortality (0-7%; summated mean ± SD, 1.6 ± 2.0% in 1118 patients),61,65,68-75 infrequent iatrogenic SAH (0%-4%; summated mean, 2.2% in 883 patients), acceptable incidence of thrombotic complications, including acute thrombosis in 1% to 13%61,65,68-75 (summated mean, 5.0% in 1118 patients), and delayed thrombosis in 0% to 3%.70,71,73,75 It is worth noting that many complications in reported series occurred early in the experience, before modifications to the stent and delivery system were introduced.
The Enterprise stent, first introduced in 2007, is a self-expanding, laser-cut nitinol hypotube closed-cell stent with radiopaque markers at both ends (Figure 6). It is available in a single diameter of 4.5 mm to treat vessel diameters from 2.5 to 4.0 mm in 4 lengths from 14 to 35 mm. It is delivered through a 0.021-in inner diameter microcatheter and has undergone no significant design changes since its introduction. Two prospective studies have been performed to assess the safety of the Enterprise stent for treatment of wide-necked aneurysms. A European study conducted between December 2003 and February 2005 included 30 patients with 31 wide-necked aneurysms, 10 of which had undergone previous treatment with detachable coils without stenting.76 SAH was the presenting diagnosis in 13 patients, although 12 of these patients were treated several months after the hemorrhage. Procedural neurological complications were limited to 1 patient with acute in-stent thrombosis ultimately requiring extracranial-to-intracranial bypass to relieve ischemic symptoms. Six-month follow-up in 29 patients yielded recanalization in 6 aneurysms, 4 of which were retreated. An unpublished study conducted at 5 centers in the United States included 28 patients with 28 wide-necked aneurysms.77 Previous intracerebral hemorrhage was present in 5 patients. Major procedural neurological complications were reported in 3 patients (12%) and included 1 death (attributed to the presenting intracerebral hemorrhage), 2 intracranial hemorrhages, and 1 cerebral infarction. Aneurysm recanalization was reported in 2 patients. On review of this study, the FDA granted approval for use of the Enterprise stent in 2007. Several retrospective studies of patients treated with the Enterprise stent (including between 46 and 218 patients) have displayed efficacy of obliteration (50%-89%68,74,78,79), with low perioperative mortality (0-3%; summated mean ± SD, 1.4 ± 1.3% in 350 patients68,74,78,79), infrequent iatrogenic SAH (1%-2%; summated mean, 1.4% in 350 patients68,74,78,79), acceptable incidence of thrombotic complications, including acute thrombosis in 0% to 9% (summated mean ± SD, 3.8 ± 4.5% in 422 patients55,68,74,78,79), and delayed thrombosis or symptomatic stenosis in 3%.55
No trial has directly compared the Neuroform and Enterprise stents for the treatment of cerebral aneurysms; however, 2 studies have reported single-center experiences with the two stents.68,74 Izar et al74 reported a consecutive series of 86 patients with 93 aneurysms for which intracranial stenting was planned. Ultimately, stents were placed in the treatment of 84 aneurysms. Those authors reported similar outcomes between patients undergoing Enterprise or Neuroform stenting, except that the Neuroform was unable to be delivered in several cases (9 of 51 attempts), and in several cases, the Enterprise was placed when placement of a Neuroform stent failed. Perioperative complications (6% and 4%), packing density (38% and 36%), and aneurysm recurrence (11% and 15%) were similar for the Neuroform and Enterprise stents, respectively. Kadkhodayan et al68 reported a consecutive series of 258 patients treated with stent-assisted coiling. These authors found more delivery failures with the Neuroform stent (41 failures in 214 attempts, 19%) compared with the Enterprise stent (7 failures in 115 attempts, 6%). In addition, immediate aneurysm occlusion was higher in the Enterprise stent cohort (87%) compared with the Neuroform stent cohort (73%). These findings are attributable to the relative ease of delivery of the Enterprise compared with the Neuroform (particularly early versions of the neuroform), as well as superior aneurysm neck coverage resulting from “gator backing” (the struts of the deployed stent may flair outward along the convexity of a curved vessel and protrude into the aneurysm dome) that occurs with the open-cell Neuroform but not the closed-cell Enterprise58 and potentially an improved ability for aneurysm packing with the Enterprise compared with the Neuroform (in this study, the authors did not report coil packing density data). Acute thromboembolic events were noted in 10 patients (8.7%) treated with the Enterprise (including 3 ischemic strokes) and 3 patients (1.4%) treated with the Neuroform (all presented with transient ischemic attack). An increased incidence of thromboembolic events with the Enterprise stent has not been reported otherwise. Theoretically, thromboembolic events may be associated with inferior vessel wall apposition and ovalization of the closed-cell Enterprise compared with the open-cell design of the Neuroform.58,80
A novel self-expanding stent laser-cut from ultrathin film nitinol hypotubes has been developed and is currently the subject of an ongoing clinical trial81 (Liberty stent, Penumbra, Inc). Compared with the Neuroform (0.066-mm thickness82) and Enterprise (0.042-mm thickness82) stents, the Liberty stent is cut from a nitinol hypotube as thin as 0.005 mm.83,84 The theoretical benefits of this stent include ease of delivery and less thrombogenicity because of its thinner metal structure.85,86 The present review predates the publication of clinical data relevant to this stent, although this advancement in technology would ideally reduce the incidence of iatrogenic perforation and thromboembolism associated with other intracranial stents used for aneurysm neck reconstruction.
Braided or Woven Stents
Another class of intracranial sent is the woven or braided stent. Woven stents are made up of a nitinol fiber (approximately 0.05 mm in diameter) woven into a cylindrical shape. These stents have an intermediate amount of parent vessel coverage (approximately 15%), significantly more than the Neuroform or Enterprise stents (approximately 5%-10% parent vessel coverage) but significantly less than the 30% coverage offered by flow-diversion stents (flow-diversion stents are described in greater detail below). This theoretically provides superior protection of the parent vessel at the aneurysm neck as a result of smaller free-cell areas. No woven stent is presently approved by the FDA for use in the treatment of intracranial aneurysms. One such stent is the Leo (Balt, Montmorency, France), which received Conformité Européenne marking in 2003.76 The closed-cell design of the Leo stent allows it to be retrieved after up to 90% deployment, and radiopaque markers along the length of the stent allow superior visualization of this stent compared with the Enterprise and Neuroform stents. European and Asian case series have displayed the efficacy and safety of this stent when used to treat wide-necked and fusiform aneurysms. Analysis of 7 small retrospective series (9-28 aneurysms per series)87-93 using the Leo stent for aneurysm neck reconstruction displays a summated obliteration rate of 65% (in 75 of 116 aneurysms87-89,91-93) with low rates of reported recurrence (5 instances in 65 patients, 7.7%89,90,93); complications were reported in 8.9% (11 in 123 patients87-93), most frequently thromboembolic complications in 8.1% (10 in 123 patients87-93), and two cases of symptomatic vessel occlusion were reported (2.9%, long-term follow-up available for 69 patients87,89,90,93). Although braided stents are designed for use with detachable coils, several reports of aneurysm obliteration after Leo stent placement alone exist.88,93-96
A similar stent, the Low-Profile Visualized Intraluminal Support (LVIS, MicroVention-Terumo) device, is a self-expanding stent made up of woven or braided 56-µm nitinol wires97 (Figure 7). It is similar in design to the Leo stent, with radiopaque markers along the entire length of the stent. In addition to improved visibility and navigability, the theoretical advantage of this stent compared with the Neuroform and Enterprise stents is its smaller free-cell area (roughly 0.9 mm in diameter,97 compared with the roughly 2-mm free-cell diameter of the Leo stent and 1.5 × 3.0-mm free-cell area of the Enterprise stent), which allows superior protection of the parent vessel.98 An experimental study of this stent implanted in constructed bifurcation aneurysms in a canine model reported superior aneurysm obliteration when stents were used in conjunction with coils vs simple coiling that was due, in part, to neointimal formation associated with the stent.97 Preliminary clinical reports of LVIS use have been promising.98 A smaller version of this stent (LVIS Jr) may be delivered through a 0.0165-in inner diameter microcatheter. These stents are investigational devices in the United States.
Complex Stent Reconstruction
Wide-necked aneurysms located at large vessel bifurcations remain relatively difficult for endovascular treatment because stent reconstruction may require placement of 2 stents (Y stenting99,100) or placement of the distal end of the stent within the aneurysm dome (waffle cone technique101). Several reports of various complex stent/coil treatment strategies exist for wide-necked aneurysms of the basilar terminus, middle cerebral artery, and anterior communicating artery complex; however, most are case reports or small series. The risk of perioperative complications with such a procedure remains unknown and not insignificant, likely underreported, and likely greater than that of conventional stent deployment or placement of a single stent. Bifurcation stents designed for the cerebral vasculature are not available for use at this point; however, nonstent devices for aneurysm neck reconstruction (Figure 8) have shown promise in the treatment of wide-necked bifurcation aneurysms in vitro or in small series or case reports102-105 and may represent a superior option with less material implanted into the parent and daughter vessels of a bifurcation aneurysm.
ADVANCES IN FLOW-DIVERSION TECHNIQUES
With the advent of self-expanding intracranial stents to provide aneurysm neck remodeling during coiling of wide-necked aneurysms, a new frontier in the endovascular management of intracranial aneurysms was born. Improved outcomes with stent-assisted coiling were found to be associated with stent-induced modifications of blood flow within and around the aneurysm itself, along with its expected benefit as a mechanical scaffold in providing denser aneurysm packing with coils.106,107 Further investigation into this phenomenon led to the concept of flow diversion, which is based on the premise of uncoupling blood flow between the parent vessel and the aneurysm, leading to progressive aneurysm thrombosis and involution. Essentially, stents made with lower porosity, increased pore density, and higher metal coverage (30%-50%) were found to significantly reduce the flow of blood into an aneurysm,108,109 leading to its progressive thrombosis. Flow diversion represents the endovascular correlate of surgical clipping, in which the treatment focuses on isolating the aneurysm from the parent circulation with restoration of parent vessel continuity, as opposed to the standard endosaccular approach of filling the aneurysm with coils. This is a fundamental paradigm shift in the endovascular management of intracranial aneurysms.
Therefore, the flow-diversion strategy aims at decreasing the flow of blood into the aneurysm by placing a high-metal-content, low-porosity stent across the aneurysm neck, leading to gradual intra-aneurysmal blood flow stagnation, thrombosis, and subsequent atrophy of the aneurysm. In addition, flow diversion leads to progressive neointimal remodeling of the parent vessel, further eliminating the aneurysm from the circulation.108,110,111 Because the mechanism of action of flow diverters is independent of aneurysm or neck size, dome-to-neck ratio, or need for dense coil packing, these devices seem particularly well suited for the treatment of large or giant, wide-necked, fusiform, or blisterlike aneurysms. These aneurysms do not have an optimal surgical or endovascular treatment alternative and represent a particularly poor prognosis subset of intracranial aneurysms. In the case of giant aneurysms, for instance, surgical mortality rates remain as high as 10%, and surgical morbidity rates approach 30%, despite the development of skull base approaches and surgical bypass strategies.112-115 Traditional endovascular techniques (primary coiling or stent-assisted coiling) have so far been unable to provide a better solution for treatment of these lesions, with aneurysm occlusion rates of only 57% and an overall mortality rate varying between 7.7%116 and 11%.117,118 The natural history of giant intracranial aneurysms is also dismal, with 5-year cumulative rupture rates of 40% in the anterior circulation and 50% in the posterior circulation.119
There are currently 2 flow-diverter devices approved for use in the treatment of intracranial aneurysms in the market: the Pipeline Embolization Device (ev-3 Covidien, Mansfield, Massachusetts) and the Silk Flow Diverter (Balt Extrusion, Montmorency, France). The Pipeline device is a flexible, meshlike tube of 48 interwoven microfilaments consisting of 25% platinum-tungsten and 75% cobalt-chromium-nickel alloy, designed to provide 30% to 35% metal coverage of the inner surface of the target vessel, with a pore size of 0.02 to 0.05 mm2 at the nominal vessel diameter120 (Figure 9). The device is available in sizes ranging from 2.5 to 5.0 mm in diameter (in 0.25-mm increments) and 10 to 35 mm in length (in 2-mm increments between 10 and 20 mm and 5-mm increments between 20 and 35 mm). When fully deployed, it remains very flexible and able to conform to tortuous vessel anatomy. The Pipeline was granted approval in Europe in 2008 and in the United States in 2011. The Silk flow diverter is also a flexible mesh stent; it is constructed from 48 braided nitinol and 4 platinum microfilaments, with a pore size of 110 to 250 µm and 35% to 55% metal coverage at its nominal vessel diameter.121 The Silk device is available in sizes ranging from 3.0 to 5.5 mm in diameter and 15 to 40 mm in length. This device received approval for use in Europe in 2008. Instructions for use of both devices are similar, with the exception that adjunctive use of endosaccular coils is recommended for the Silk and this device can be retrieved if < 90% of its length has been deployed. Both devices are delivered via a microcatheter (0.027 in for the Pipeline; 0.023 in for the Silk) by a combination of pushing the delivery wire and unsheathing the microcatheter. Both devices require a 6F guide catheter. Several Pipeline devices can be deployed in an overlapping fashion to increase the metal area coverage of a particular aneurysm or to ensure proper coverage of a longer vessel segment.
Four major prospective studies have described the results of utilization of the Pipeline device for treatment of intracranial aneurysms: the Buenos Aries122 and Budapest123 case series, the Pipeline Embolization Device for the Intracranial Treatment of Aneurysms (PITA) trial, and the Pipeline for Uncoilable or Failed Aneurysms (PUFS)124 trial. The Buenos Aires study described 53 patients with 63 aneurysms (33 small, 22 large, and 8 giant aneurysms) treated with the Pipeline device over a 26-month period.122 Complete angiographic occlusion was achieved in 56% of aneurysms at 3 months, 93% at 6 months, and 95% at 12 months. No patient experienced a major complication (such as stroke or death) during the study period. The Budapest study described 19 wide-necked aneurysms treated by the Pipeline device either alone (n = 10) or with coils (n = 9).123 At the time of 6-month follow-up angiography, 17 of 18 aneurysms were completely occluded. Four patients experienced neurological complications: 2 patients recovered completely, 1 patient had permanent morbidity, and 1 patient died. The PITA trial comprised 31 cases of unruptured aneurysms that were wide-necked, had unfavorable dome-to-neck ratios (< 1.5), or had failed previous therapy and were then treated by the Pipeline device either alone (n = 15) or with coils (n = 16).125 Follow-up angiography demonstrated complete aneurysm occlusion in 93.3% (28 of 30 aneurysms) at 6 months, with 2 periprocedural strokes. The PUFS trial was a multicenter, prospective, single-arm trial of Pipeline treatment of wide-necked aneurysms of the internal carotid artery, which are conventionally difficult to treat with detachable coils.124 It demonstrated an occlusion rate of 73.6% (78 of 106 aneurysms) at 6 months without the use of adjunctive coils. Six of 107 patients (5.6%) developed major ipsilateral stroke or died during the 6-month follow-up period. On the basis of the PUFS trial results, the Pipeline device was granted FDA approval for the endovascular treatment of adults (≥ 22 years of age) with large or giant wide-necked intracranial aneurysms of the internal carotid artery from the petrous to the superior hypophyseal segments.
Because of the inherent thrombogenicity associated with intracranial stents, all patients considered for flow-diversion treatment need to be pretreated with a dual antiplatelet regimen. Before flow-diverter implantation, patients receive a loading dose of aspirin and clopidogrel; then the pharmacological responses to these agents are checked and doses are optimized until appropriate therapeutic responses are obtained. Patients are kept on dual antiplatelet agents for at least 6 months, after which time clopidogrel is usually discontinued. Patients are kept on aspirin for life. Despite the low porosity and high metal content of the Pipeline device, outflow through perforating branches is usually maintained, as long as there is a pressure gradient from a high-pressure parent artery to a low-pressure venous system. However, use of the Pipeline device in a perforator-rich vascular territory such as the vertebrobasilar system inspires caution, given the possibility of occlusion of perforating branch vessels, especially should placement of > 1 device become necessary.126
As more experience is gained with use of flow-diversion devices for treatment of intracranial aneurysms, possible risks and complications involved with this new technology have become better acknowledged if not yet completely understood. Device-related delayed aneurysmal rupture, thromboembolic complications with ischemic strokes, nonaneurysmal intracranial hemorrhages, and worsening of mass effect symptoms have all been documented in recent literature.108,127,128 Delayed aneurysmal rupture is of great concern, given the fact that aneurysmal thrombosis with eventual occlusion is a gradual process after treatment with flow diverters. In a review of 5 prospective case series of Pipeline-treated aneurysms, the incidence of delayed hemorrhage was 2%.108 The underlying mechanism remains unclear; among different hypothesis are redirection of blood flow within an “unstable” aneurysm or inflammatory changes related to the formation of the intra-aneurysmal clot, with subsequent aneurysmal wall destabilization and rupture.108,128 In a review of 13 cases of delayed aneurysmal hemorrhage after flow diversion with the Silk device, Kulcsár et al127 hypothesized that changes in intra-aneurysmal flow patterns may have favored the formation of autolytic thrombus, ultimately leading to degradation of the aneurysm wall and rupture. This work underscores how much is still unknown about the effects of flow diversion in an individual aneurysm and how parent vessel geometry and aneurysm flow patterns may influence the final outcome of a treatment. In a systematic review of the literature concerning intracranial aneurysms treated with the Pipeline device, Leung et al128 described an overall complication rate of 6.3% (for intracranial vascular events such as stroke or hemorrhage) and an overall mortality rate of 2.2%.
Although the pertinent literature documents several limitations associated with flow diversion at present such as reduced efficacy in previously treated aneurysms, need for dual antiplatelet therapy (which poses a problem for treatment of ruptured aneurysms), and inability to treat distal bifurcation aneurysms (such as middle cerebral artery bifurcation or anterior communicating artery aneurysms), this technology will likely evolve fairly quickly, and many of its current limitations and associated complications will be solved by further product refinements. As further experience with flow diverters is accumulated and current devices evolve, it is likely that flow-diversion therapy will have an ever-widening range of applications, including the treatment of ruptured aneurysms, blister aneurysms, dissecting aneurysms, and distal bifurcation aneurysms.
Intraluminal flow-diversion devices have been developed, and limited clinical experience has been reported. Composed of braided nitinol wire (similar to flow-diversion stents), these devices are 3-D implants designed to be detached within the lumen of a cerebral aneurysm. When in place, they divert blood flow into the aneurysm and encourage thrombosis within the aneurysm. The principal benefit of these devices compared with stent-like flow-diversion devices is the lack of implanted material within the parent vessel. Antiplatelet medication is thus rendered unnecessary, and the risk of thromboembolism is minimal by comparison. Two such devices, the Woven Endo-Bridge (Sequent Medical, Aliso Viejo, California) and Luna (Covidien Vascular Therapies, Irvine, California; Figure 10), have been studied in vitro with promising results129,130; clinical experience, although limited, has been favorable.131,132 These devices are ideally suited to treat bifurcation aneurysms, which are currently unable to be safely treated with flow-diversion stents.
ADVANCES IN PHARMACOLOGICAL MANAGEMENT OF ANEURYSMS
With more widespread use of stent-assisted coiling and the more recent use of flow-diversion strategies with stentlike devices, the concept of antiplatelet resistance has become relevant for the neurointerventionalist. Our understanding of antiplatelet resistance (mainly aspirin and clopidogrel, which are the 2 most commonly used antiplatelet pharmacological agents) and its association with thromboembolic events comes primarily from the cardiac literature. Up to 30% of patients are found to be “resistant” to conventional doses of clopidogrel, whereas inadequate antiplatelet response to aspirin is less common and affects only 3% to 5% of patients.133-135
Emerging evidence suggests that variations in the degree of antiplatelet response are associated with both thromboembolic (in nonresponders) and bleeding (in overresponders) complications in conjunction with neurointerventional procedures. Thromboembolic complications, including intraoperative and postoperative in-stent thrombosis, are more commonly observed in patients with resistance to clopidogrel.136-138 An increased bleeding risk was found in patients undergoing endovascular treatment of intracranial aneurysms who were taking antiplatelets and exhibited a hyperresponse to clopidogrel.136,139 In that group of patients, the rate of major bleeding complications was 43%, including intraparenchymal hemorrhages and SAHs. When antiplatelet resistance is encountered in clinical practice, possible solutions can include administering an extra (reloading) dose of the same agent, using new agents such as prasugrel and ticagrelor, and minimizing interactions with agents known to decrease antiplatelet efficacy such as proton pump inhibitors.140,141
ADVANCES IN NONINVASIVE FOLLOW-UP IMAGING
Imaging follow-up is imperative for confirmation of adequate occlusion of the aneurysm with coil mass and timely recognition of aneurysm residual or new aneurysm growth and patency of the stent in cases of stent-assisted coiling or flow diversion. Because of the cost and invasive nature of conventional angiography, noninvasive studies are often the preferred follow-up modality.
Magnetic resonance (MR) angiography demonstrates high negative predictive value in assessment of occlusion of aneurysms treated with coil placement.142,143 Therefore, when complete occlusion is seen on an MR angiogram, no further investigation with DSA is required. However, because of the low positive predictive value of this imaging modality, aneurysm recurrence identified with MR angiography would require confirmation with DSA.
Contrast-enhanced MR angiography allows improved visualization of contrast filling within the coil mass and is associated with fewer artifacts, thus enhancing the diagnostic accuracy of MR angiography.144,145 For assessment of intracranial aneurysms after stent-assisted coiling, MR angiography can significantly exaggerate stenosis of the stented parent artery, even when contrast-enhanced MR angiography is used.146
CT angiography is another noninvasive imaging modality that is commonly used for follow-up assessment. It requires administration of iodinated contrast material, requires exposure to radiation, and is often used as an alternative to MR angiography in patients with pacemakers and defibrillators or other contraindications to MR studies. Multidetector CT angiography offers higher resolution than conventional CT angiography.147,148 In fact, 320-detector-row CT angiography provides whole-brain coverage with high sensitivity and specificity of diagnosing intracranial aneurysms, especially those > 3 mm in size.149 In addition, CT angiography can demonstrate the presence of calcifications and surrounding bony anatomy.
Contemporary endovascular treatment of cerebral aneurysms requires knowledge of many technologies. Such technologies and devices have enabled treatment of a wider variety of intracranial aneurysms. More advancements in endovascular treatment of aneurysms should be expected that will render many contemporary devices and techniques obsolete. Ultimately, all intracranial aneurysms may be optimally treated with endovascular techniques, with the exception of those presenting with rupture causing life-threatening mass effect. It is our expectation that refinements in technology and technique will decrease the incidence of perioperative complications and aneurysm recurrence associated with endovascular techniques.
A podcast associated with this article can be accessed online (http://links.lww.com/NEU/A605).
Dr Levy receives research grant support (principal investigator, Stent-Assisted Recanalization in Acute Ischemic Stroke [SARIS]), other research support (devices), and honoraria from Boston Scientific* and research support from Codman & Shurtleff, Inc and ev3/Covidien Vascular Therapies; has ownership interests in Intratech Medical Ltd and Mynx/Access Closure; serves as a consultant on the Board of Scientific Advisors to Codman & Shurtleff, Inc; serves as a consultant per project and/or per hour for Codman & Shurtleff, Inc, ev3/Covidien Vascular Therapies, and TheraSyn Sensors, Inc; and receives fees for carotid stent training from Abbott Vascular and ev3/Covidien Vascular Therapies. Dr Levy receives no consulting salary arrangements. All consulting is per project and/or per hour. Dr Mokin has received an educational grant from Toshiba Medical System Corp. Drs Dumont, Eller, and Sorkin report no financial relationships. (*Boston Scientific's neurovascular business has been acquired by Stryker.)
We thank Paul H. Dressel, BFA, for preparation of the illustrations and Debra J. Zimmer for editorial assistance.
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Cerebral aneurysm; Coil; Endovascular technique; Endovascular technology; Flow diversion; Stent; Subarachnoid hemorrhage
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