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Current Status of Pipeline Embolization Device in the Treatment of Intracranial Aneurysms: A Review
Current Status of Pipeline Embolization Device in the Treatment of Intracranial Aneurysms: A Review Mona M.Y. Tse1, Bernard Yan2,3, Richard J. Dowling1, Peter J. Mitchell1
Key words Intracranial aneurysms - Pipeline embolization device -
Abbreviations and Acronyms DSA: Digital Subtraction Angiography OKM: O’KellyeMarotta PED: Pipeline embolization device 1
From the Neurointervention Service, Department of Radiology, and 2Comprehensive Stroke Centre, Royal Melbourne Hospital, Melbourne, Victoria; and 3Melbourne Brain Centre, University of Melbourne, Parkville, Melbourne, Victoria, Australia To whom correspondence should be addressed: Mona M.Y. Tse, M.B.B.S., F.H.K.C.P. [E-mail: [email protected]] Citation: World Neurosurg. (2013) 80, 6:829-835. http://dx.doi.org/10.1016/j.wneu.2012.09.023 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2013 Published by Elsevier Inc.
INTRODUCTION The treatment of endovascular aneurysm has evolved considerably during the past two decades, with coiling emerging as the treatment of choice for a significant proportion of saccular aneurysms (17). The International Study of Subarachnoid Aneurysm Treatment (24) and the Barrow Ruptured Aneurysm Trial (23) have established the advantages of endovascular treatment in selected clinical scenarios. However, a considerable number of aneurysms are not amendable to coiling. Balloon remodeling and stent-assisted techniques were developed in mid-1990s and early 2000, rendering more feasible the treatment of aneurysms with more complex morphology (17). Despite the technological advances, wide-neck and giant saccular or fusiform aneurysms present considerable challenges for the operator (13). Parent artery occlusion is one of the earliest endovascular techniques that showed efficacy treatment for unclippable giant aneurysms. However, parent artery occlusion depends on patient tolerance to occlusion,
- OBJECTIVE:
Pipeline embolization device (PED) implantation is a novel endovascular treatment option for the treatment of intracranial aneurysms. It is emerging as a useful alternative to coiling and to open surgery, and its use is increasing worldwide. We performed a literature review to examine its efficacy, technical challenges, and safety.
- METHODS:
PubMed database was used to identify all articles relating to PED.
- RESULTS:
The review outlines the indications for PED, its technical aspects, complications, and clinical outcomes.
- CONCLUSIONS:
PED offers an alternative to endovascular coiling for aneurysms with complex morphology. The indication for its use has evolved from the limited scope of treatment of giant aneurysms with wide necks to the inclusion of smaller aneurysms. The procedural safety profile of PED is comparable with or possibly superior to balloon-remodeling or stent-assisted coil embolization in specific circumstances. However, questions remain regarding the incidence of post-procedural subarachnoid hemorrhage. Ongoing monitoring and meticulous documentation of PED postimplantation safety is strongly recommended.
and reliable predictors for ischemic events are lacking. (13) Furthermore, successful balloon occlusion test does not preclude delayed ischemic complications that occur between 4% and 15% of cases. (13) Endovascular treatments frequently fail to produce complete occlusion in such aneurysms (1). Recurrence of the treated aneurysm postendovascular treatment occurs in 9% to 34% cases (1, 3-5, 25, 30). Incomplete occlusion, larger (>10 mm) aneurysm size, and neck size are risk factors for recurrence (1, 3-5, 25, 30). These aneurysms are prone to coil compaction and recanalization, even when complete or near-complete occlusion has been achieved after the initial embolization, and require extended imaging surveillance and the possibility of retreatment (12, 24, 25, 35). Failure of endovascular techniques to achieve a complete and durable occlusion of aneurysms has been attributed to several factors, including limitations with respect to the volumetric packing of the aneurysm sac with coils, inherent difficulties associated with achieving a continuous reconstruction of large complex aneurysm neck
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defects with coils, and finally a fundamental failure of the endovascular strategy to address the underlying diseased parent vessel (9). MATERIALS AND METHODS Literature Review A search for published articles on pipeline embolization devices (PED) in PubMed between 2000 and February 2012 was performed. A total of 210 patients with 241 aneurysms treated with PED were identified in five reported case series. A detail review on the indications, therapeutic results, and technical and safety issues of PED was performed. Principle of Flow Diversion Flow diversion offers a fundamentally novel treatment approach. This approach potentially represents a more physiologic treatment of intracranial aneurysms in comparison with coil embolization. Flow-diversion devices produce both haemodynamic and biological effects, namely (1) flow redirection promoting flow stasis
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and thrombosis in the aneurysm and (2) tissue overgrowth where the stent provides a scaffolding for the development of endothelial and neointimal tissue across the aneurysmal neck (29). By redirecting blood flow along the normal course of the parent artery, flow-diversion devices markedly alter dynamic fluid exchange across the aneurysm/ parent vessel interface, creating an intra-aneurysmal environment that is conducive to thrombosis (14, 15, 31). After successful aneurysm thrombosis, the construct becomes progressively incorporated into the parent artery through a process of neointimal overgrowth, and a continuous, homogeneous layer of tissue unites the normal parent artery segments proximal and distal to the aneurysm neck defect, completing the process of endoluminal reconstruction (14, 15, 31). This step ultimately results in the anatomic exclusion of the aneurysm from the circulation and promotes final involution of the aneurysmal mass as the intrasaccular thrombus is resorbed. PED PED (ev3, Irvine, California, USA) is a flexible self-expanding, microcatheter-delivered, high-metal-surface-area coverage, stent-like device designed to achieve aneurysm occlusion through the endoluminal reconstruction of the diseased segment of the parent artery that gives rise to the aneurysm (Figure 1). Composed of 48 individual cobalt chromium and platinum strands, it provides 30% to 35% metal surface area coverage when fully deployed (10), in comparison with only 6% to 9.5% coverage with conventional bare metal stents (e.g., Neuroform stent; Boston
Figure 1. Pipeline embolization device (Ev3, Irvine, California, USA).
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Scientific/Target Therapeutics, Fremont, California, USA) and 12% to 16% with balloon-mounted stents (21). Devices are available with a nominal diameter from 2.5 to 5 mm with 0.25-mm increments. The nominal length of the implants is in the range from 10 to 35 mm in 2-mm increments. At the nominal diameter, the pore size is 0.02 to 0.05 mm2, and the radial force is approximately 2.0 mN/mm (3.0 mm vessel diameter). PED is premounted on a stainless-steel wire with a radiopaque 15-mm platinum tip extends beyond the end of the PED and is delivered via a 0.027-inch ID microcatheter. PED has received the Conformité Européene mark of approval on the basis of the Pipeline Embolization Device for the Intracranial Treatment of Aneurysms (PITA) trial (27) and has been sold outside the United States since July 2009. On the basis of the results of the Pipeline for Uncoilable or Failed Aneurysms (PUFS) clinical study that included safety and efficacy data on 108 patients, in April 2012, PED received premarket approval from the U.S. Food and Administration for the endovascular treatment of adults (>22 years of age) with large or giant, widenecked intracranial aneurysms of the internal carotid artery from the petrous to the superior hypophyseal segments. Compassionate use of PED is allowed in patients who meet the criteria for treatment but do not qualify for the inclusion criteria in PUFS study because of their age or the location of the aneurysm and for whom there are no other reasonable alternative treatments.
RESULTS Aneurysm Selection and Limitations With larger patient series being published recently, confirming the efficacy of the device and its safety profile, the use of PED has transformed during the past few years from a novel, investigational device reserved for otherwise-untreatable lesions to a more established alternative technique that is being integrated into routine cerebrovascular practice (6). A transition in the use of PED in treating large and giant aneurysms to include small- to mediumsized aneurysms has been observed. Large to giant, broad-necked aneurysms comprised the majority of aneurysms
treated in previous studies. In these studies, mean diameter and neck size of treated aneurysms was between 11.1 to 16 mm and 5.8 to 7.4 mm, respectively (21, 27, 33); 48% to 73.3% of these aneurysms were greater than 10 mm compared with mean aneurysm sizes of 3.8 to 5.13 in later studies (Table 1) (11, 19). In more recent studies, small- to medium-sized aneurysms were the target aneurysm size. Lubicz et al. (19) and Fischer et al. (11) each recruited patients with aneurysms greater than 10 mm in only 11.1% and 2.9%, respectively, with 59% and 48.5%, respectively, less than 5 mm. Forty-four to 66% were recurring aneurysms (Table 1) (11, 19). The differences in these aforementioned studies highlight a gradual transition of PED from being an investigational device in treating large and giant aneurysms to a standard treatment options for recurring or de novo aneurysms in the size range encountered more commonly in clinical practice. Very small or blister aneurysms (<2 mm) pose a different challenge for conventional endovascular coiling because both catheterization and the need of endovascular coil placement have increased risk of procedural rupture, especially in curved vessels. Martin et al. (22) reported a patient with aneurysms smaller than 2 mm who presented with acute subarachnoid hemorrhage and was successfully treated with PED. PED may offer an attractive alternative method in treating these patients with very small or blister aneurysms, potentially reducing risk of periprocedural rupture. Despite the fact the size range of aneurysms treated with PED has increased dramatically during the past 2 years, the clinical indications remains largely unchanged, that is, (1) for wide neck aneurysms with high likelihood of failure with conventional endovascular therapy or microsurgery; (2) to treat remnants of aneurysms after clips and coiling treatment; (3) fusiform aneurysms; and (4) dissecting aneurysms. PED has two major limitations in its application. First, because it originally was designed for sidewall aneurysms, its use in bifurcation aneurysms has been limited. The potential use with a “kissing” implantation of two PEDs or in combination with conventional stents to create a bidirectional flow diversions has not been fully evaluated. Second, the associated delayed aneurysm
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Table 1. Summary of Aneurysms Characteristics Treated with PED Across Various Studies Authors
Lylyk et al., 2009 (21)
Szikora et al., 2010 (33)
Journal
Neurosurgery 2009
American Journal of Neuroradiology
Number of patients/ aneurysms
53/63
18/19
Morphology
33 (<10 mm)
5 (<10 mm)
20 (<10 mm)
13 (<5 mm)
49 (<5 mm)
22 (1025 mm)
10 (1025 mm)
9 (1025 mm)
11 (510 mm
11 (510 mm)
8 (>25 mm)
4 (>25 mm)
2 (>25 mm)
3 (>10 mm)
3 (>10 mm)
Mean size 5.13 mm 13/20 (65%) has wide neck
Mean size 3.8 mm (215 mm) Neck 3.3 mm (215 mm)
12 (44.4)
54 (53)
Mean size 11.1 mm (3.530 mm) Neck size >4 mm in 100% of cases Recurrence, n (%)
23 (37)
thrombosis and the need for dual antiplatelet after treatment makes PED unsuitable for ruptured aneurysms in acute phase. The use of PED treating ruptured dissecting or blister aneurysms in acute situation, however, has been reported in recent two case reports (22, 26). Technical Challenges PED differs from other intracranial stents, such as Neuroform (Boston Scientific/ Target Therapeutics) or Wingspan (Boston Scientific/Target Therapeutics) in some aspects, presenting several distinct technical challenges in clinical practice. First, the delivery catheter must recross the Pipeline device over the delivery wire to recapture the distal coil tip after complete stent deployment. Second, significant foreshortening is noted in PED. Up to 50% foreshortening is expected when fully deployed compared with 1.5% to 7.1% and 1.8% to 5.4% foreshortening in Wingspan and Neuroform stents, respectively. The longest available length of the device is 35 mm, which makes reconstruction with telescoping PEDs necessary to cover the entire length of large fusiform or dissecting aneurysms. This potentially increases the risk of arterial branch or perforator occlusion in the overlapped segment. Special attention to these distinctive features of PED is essential to enable successful PED deployment and placement. Device Deployment. Device deployment is successful consistently in 87% to 100% across many studies (11, 19, 21, 27, 33).
Mean size 16 mm Mean neck size 7.4 mm (418 mm) 1 (5.3)
Nelson et al., 2011 (27) American Journal of Neuroradiology 31/31
Mean size 11.5 mm Mean neck size 5.8 mm 71% neck >4 mm 12 (38.7)
Earlier studies have slightly lower success rates of 87% to 97% (21, 27, 33) in contrast to near 100% (99%100%) in more recent series (11, 19). This difference likely reflects technical improvement over time. There were a total of eight PED deployment failures reported in two series. All of these were encountered when PED was deployed across very tortuous vessels, which created excessive friction (27, 33). Problems in recapturing the distal coil tip of the delivery wire are not uncommon. Lylyk et al (21) reported one (1.5%) case where the distal coil tip fractured and became engaged in the deployed PED. Lubicz et al. (19) reported seven (25%) other failures to recapture the distal coil tip. Selection of Device Diameter and Length. Selection of the appropriate diameter and length of the device is essential to ensure proper stent function and to minimize the chance for unanticipated stent shortening or migration. Allowance for the anticipated foreshortening of approximately 50%, and possible device shift during deployment is critical when choosing the length of the device (20). There is a potential risk of an endoleak-like phenomenon with implantation of an undersized device, which results in poor wall apposition. Similarly, implantation of an oversized device may result in poor coverage of the lesion because of an incomplete compaction of the strands (11). These problems can affect the overall efficacy of PED. The diameter of the proximal segment of the target vessel and the
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Lubicz et al., 2011 (19)
Fischer et al., 2012 (11)
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20/27
88/101
diameter at the origin of the lesion determine the diameter of the PED (11). The distal vessel diameter is of lesser importance. Selection of a stent diameter 0.25 to 0.5 mm larger than the distal parent diameter is also recommended (19). The presence of existing conventional stents may complicate the delivery and deployment of PED. Fischer et al. (11) reported a greater periprocedural complication rate compared with those patients without a pre-existing stents (2% vs. 13%). Overall, the technical complications occurred in range of 3.1% to 33.3% depending upon the definition of technical complications in different studies. Most of these complications did not result in clinical significant sequelae. Angiographic Evaluation of Aneurysms After Flow Diversion Treatment. No standardized postprocedural angiographic evaluation after flow diversion placement was used in earlier studies. Lylyk et al. (21) used an “all-or-none” assessment (i.e., aneurysm fills or not) whereas Nelson et al. (27) used the three-point Raymond scale to assess the aneurysm status postflow diversion treatment. Specific periprocedural angiographic assessment postflow diverter stent placement was first described by Szikora et al. (33) and was further elaborated by O’Kelly et al. (28), who developed the O’KellyeMarotta (OKM) grading scale in 2010 aiming to facilitate communication and standardize outcomes assessment after flow diversion treatment. This scale takes into account the amount of
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aneurysm perfusion and stasis of contrast medium. Aneurysm perfusion is graded as: A, complete perfusion (>95%); B, incomplete perfusion (5%e95%); C, neck remnant (>5%); or D, no perfusion (0%). The contrast medium stagnation grade is determined by the timing of contrast medium clearance from the aneurysm sac as defined by the phases of the angiogram: 1, no stasis (clearance within the arterial phase); 2, moderate stasis (clearance before the venous phase); 3, significant stasis (contrast persists in the aneurysm into the venous phase and beyond). This scale was used in two studies in 2011 (11, 19). The duration of contrast stasis induced by a flow diverter might be a helpful tool to estimate the likelihood of complete intraaneurysmal thrombosis (28). This might also help to determine the need for more than one flow diverter during the procedure. Fischer et al. (11) indeed decided the need for more than one PED in their patients depending on the OKM grading scale. Although additional coiling did not alter the overall aneurysm thrombosis rate (33), whether the use of additional PEDs (which created a greater contrast stagnation score), translates into earlier aneurysm thrombosis and overall greater obliteration rate needs further research. Efficacy of PED Prediction of Aneurysm Occlusion. The primary aim of flow diversion treatment of an aneurysm is to induce a process of intraaneurysmal thrombus formation, with the final goal of complete aneurysm occlusion. This usually occurs between a few months and a year. Residual or even unchanged intra-aneurysmal contrast filling is an expected finding immediately after PED placement in the majority of cases, whereas immediate aneurysm exclusion is considered an uncommon occurrence. It may be presumed that aneurysm size and geometry or the total number of PEDs placed across the aneurysms neck may play a role in predicting time to aneurysmal thrombosis. In fact, immediate aneurysm exclusion has been reported by Lylyk et al. (21) and Szikora et al. (33) with 8% and 21% (3 with additional coiling), respectively, of aneurysms less than 5 mm respectively occluding immediately. In contrast to these earlier findings, Fischer et al. (11) reported no immediate
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aneurysm occlusion, despite the fact that 48% of the intracranial aneurysms were <5 mm and greater than 60% of the 101 aneurysms had multiple PEDs placed. This apparent discrepancy may be explained by the following: (1) more aggressive antiplatelet loading in Fischer group with aspirin 500 mg plus 600 mg of clopidogrel at least one day before procedure (11) compared with 100 to 325 mg of aspirin plus 75 mg of clopidogrel 48 to 72 hours before in other studies; (2) the geometry of the aneurysm may be a more important determining factor than size; and (3) the heterogeneity and small sample size in all the studies made meaningful statistic analysis difficult. To date, there are no identifiable procedural techniques or aneurysmal characteristics that reliably predict earlier aneurysm thrombosis and higher exclusion rates. Aneurysm Occlusion Rate. The overall aneurysms occlusion rate has been very promising, with more than 50% (range, 52%56%) at 3 months, around 90% (84%94%) at 6 months and greater than 95% at 12 months (95%100%; Figure 2). Occlusion rates of 56%, 93%, and 95% at 3, 6, and 12 months were reported by Lylyk et al. (21). Szikora et al. (33), Nelson et al. (27), and Lubicz et al. (19) reported complete occlusion rates of 94%, 93.3%, and 84% by 6 months. A total of 100% occlusion at 12 months was achieved in Nelson et al.’s group (22). Fischer et al. (11) have the lowest reported complete occlusion rate of 74% at 10 months but a comparable occlusion rate of 52% at 3 months, despite the fact that the group
had just less than half of the aneurysms under 5 mm and used multiple PEDs more than 60% of the time. The observed differences may be attributed to the extended period of dual antiplatelet therapy of 1 year compared with 6 weeks in Szikora et al.’s group (33), 1 month in Nelson et al.’s group (27), 3 to 6 months in Lubicz’s et al. (6 months if side branch was covered) (19), and 6 months in Lylyk et al.’s group (21). Prolonged dual antiplatelet treatment may significantly delay aneurysmal thrombosis. The obliteration rate of greater than 90% at 6 months achieved by PED compares favorably to endovascular coil embolization, where the highest reported complete occlusion rate was 66% in the International Subarachnoid Aneurysm Trial (24). This finding was despite the ISAT comprised aneurysms selected as suitable for coil embolization, with more than 90% small aneurysms (24). These rates of occlusion are even lower in selected subgroups such as large, giant, wide-necked, and nonsaccular aneurysms. Raymond et al. (30) also found that up to 34% of intracranial aneurysms treated with coiling recur at a mean of 12 months. Recurrence after successful PED treatment has not been reported with the available short- and medium-term data to date. Persisted or unchanged aneurysm perfusion at follow-up angiography poses a completely different and unique challenge with flow diversion treatment. Only one study addresses this issue and described the use of second PED treatment in this situation. Retreatment was performed in 8 (9%) patients with
Figure 2. Overall reported aneurysms occlusion rate versus time.
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persistent or unchanged aneurysm perfusion; final results of these patients, however, were not available (11). At present the decision to observe or to retreat these aneurysms is controversial. No evidence is currently available to guide the best treatment strategies. The additional use of coils in large or acutely ruptured aneurysms with the intention of inducing early intrasaccular thrombosis when the flow diversion effect by PED alone was thought insufficient and was not found to be associated with increased aneurysm occlusion rate (33). The two groups differ in the use of a single PED in the coil group, with multiple overlapping devices reported when PED was used alone. Lubicz et al. (19) advocate the use of additional coiling only in aneurysms with high risk of rupture or to restrict Pipeline coverage to a single device in order to minimize the risk of side branch occlusion. The presence of a previously deployed stent may reduce the hemodynamic effect of a PED (21), but Fischer et al. (11) found the occlusion rate was similar (65% vs. 69%) regardless of the presence of preexisting conventional stent. On the other hand, delayed endothelialization may be expected under these circumstances. An extended phase or lifetime-long dual platelet medication is advocated (11). Safety Aspects Current evidence supports PED as a safe device associated with low morbidity and mortality. There have been a total of 210 patients with 17 (8.1%) complications and 4 (1.9%) deaths reported. Procedural morbidity and mortality range between 4.5% and 16.6% and 0% and 5.5%, respectively. These figures are comparable with the risks of unruptured aneurysms treated by coiling. In a series of 246 patients with unruptured aneurysms treated with Guglielmi detachable coils, Murayama et al. (25) reported a 5.3% rate (13 of 246) of procedural morbidity and mortality in a group largely composed of aneurysms amenable to coiling alone. Balloon-remodeled or stent-assisted coil embolization is usually necessary in the population of aneurysms treated with PED. In a review article, Shapiro et al. (32) examined the safety of balloon-assisted or balloon remodeling coiling. They found that 443 balloon-assisted or balloon-remodeled coiled aneurysms demonstrated a morbidity
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Table 2. Reported Clinically Significant Complications, Morbidity, and Mortality Associated with Pipeline Embolization Device Treatment Across Various Studies
Complications
Lylyk et al., 2009 (21)
Szikora et al., 2010 (33)
Nelson et al., 2011 (27)
Lubicz et al., 2011 (19)
Fischer et al., 2012 (11)
Total
Mass effect
3
0
0
0
0
3
In-stent thrombosis
0
1
0
1*
2y
3
Perforator occlusion
0
0
1
0
0
1
Thromboemoblic event
0
2
0
0
0
2
Intracranial Hemorrhage
0
1y
1
2y
4y
8
3 (5)
3 (16.6)
2 (6.4)
1 (5)
4 (4.5)
13 (5.7)
Morbidity, n (%) Mortality, n (%) Morbidity and Mortality, n (%)
0
1 (5.5)
0
1 (5)
2 (2.2)
4 (1.9)
3 (5)
4 (22.2)
2 (6.4)
2 (10)
6 (6.8)
17 (8.1)
*Same patient with more than one complication. yMortality case.
and mortality of 8.1% and 1.7%, respectively, which is comparable with PED. The details of complications are outlined in Table 2. In-Stent Thrombosis. In-stent thrombosis has been reported in three patients. One occurred acutely in a patient who omitted antiplatelet before the procedure (33). Another occurred at day 5 after dual antiplatelet therapy was stopped as a result of intracerebral hemorrhage secondary to vessel wall perforation during the procedure (19). Thrombosis occurred in another patient with two telescoping PEDs placed in a pre-existing conventional stent (11). Delayed in-stent thrombosis has been reported in two patients. One occurred at 63 days after a relative short duration of dual antiplatelet therapy of 6 weeks, and resulted in death (11). Another occurred at 23 months after initial treatment with three PEDs and additional coiling, despite 6 months of dual antiplatelet followed by 12 months of high-dose (150 mg) clopidogrel (7). Currently, there are no standard guidelines or recommendations on duration and dosage of antiplatelet therapy to best prevent acute and delayed in-stent thrombosis. Dual antiplatelet agents loading before procedure and continued for a minimum of 3 months (up to 1 year in selected cases) is essential to prevent instent thrombosis. The use of prolonged dual antiplatelet therapy, however, must be balanced against the risk of delayed or
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incomplete aneurysm thrombosis and obliteration and intracranial or peripheral hemorrhage. Multiple PEDs placement appears to increase the risk of in-stent thrombosis; however, the optimal duration and regimen of antiplatelet in these situations remained to be determined. Side Branch or Perforator Occlusion. Side branch or perforator occlusion was an initial concern with multiple PEDs used in treating fusiform or dissecting aneurysms. The clinical consequences of artery occlusion are variable, with greatest risk of poor outcome likely after perforator artery occlusion. Immediate ophthalmic artery occlusion was observed after PED placement, and delayed ophthalmic artery occlusion was noted in two patients at reassessment digital subtraction angiography (DSA) at 6 months who were treated with two to four PEDs (33). Side branch occlusion at follow-up DSA was noted by Lubicz et al. (19). None of these resulted in clinical significant adverse events. Perforator occlusions seem to behave differently and are more prone to result in clinical ischaemic insult. Nelson et al. (27) reported a left basal ganglion infarct secondary to two PEDs placed in M1 segment of left middle cerebral artery with pre-existing Neuroform stent. Rooij reported another case of left basal ganglion infarction after placement of 2 telescoping PEDs in A1 segment of anterior cerebral artery (36). Both cases were thought to be
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related to occlusion of lenticulostriate arteries from M1 and A1 segments of middle cerebral artery and anterior cerebral artery, respectively. These reported cases raise the concern of using more than one PED in segments of vessels with perforators. Nelson et al. (27) recommend the overlapping of multiple PEDs in regions giving rise to eloquent perforators should be avoided. Multiple PEDs have been used to reconstruct vessels without clinical complication in other studies, with between 30-66% of aneurysms treated with multiple PEDs. No branch occlusion was observed in cases reported by Fiorella and Fischer et al (8, 11), both using 7 and 16 PEDs to reconstruct basilar trunk aneurysms respectively, with 4 to 5 complete layers of PEDs over the entire aneurysm length in one case (11). The observed discrepancy may be explained by the differences in the presence of background perforators compromised by atherosclerosis associated fusiform aneurysms compared to more conventional saccular aneurysms. Rooij and Sluzewski (36) reported the complication in a 68year-old woman in contrast to a 13-yearold girl in the case reported by Fiorella et al. (8). Intracranial Hemorrhage. Reported risk of hemorrhage after treatment with PED is relatively low (3.8%, 8 in 210 patients) but not uncommon. It is lower than all reported ischaemic events from all etiologies (4.3%). There were seven subacute intracranial hemorrhages occurring within hours to days after the procedure. They were secondary to the following: (1) rupture of a distal unprotected aneurysm in one (33); (2) parent vessel rupture in two (19, 27); (3) ipsilateral parenchymal hemorrhage in two (one patient had platelet dysfunction) (11,19); (4) from an aneurysm treated with coil and three PEDs at day 3 in one patient (11); and (5) perimesencephalic subarachnoid hemorrhage in one (19). Delayed hemorrhage was reported in one patient at 14 months after PED and 1 day after coiling occlusion of right V4 segment of vertebral artery for recurrent basilar trunk aneurysm (11). The reported hemorrhage rate is similar to conventional stent-assisted coiling embolization in unruptured aneurysms (3%) reported by Kim et al. (16). Kim et al.
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proposed the hemorrhagic transformation in the recently infarcted brain is the cause for the parenchymal hemorrhage. This may explain the two ipsilateral parenchymal hemorrhages encountered. The underlying cause for index aneurysmal rupture after flow diversion therapy is unclear at the moment. Two mechanisms have been proposed, the hemodynamic and inflammatory theory. An unfavorable valve mechanism with augmentation of inflow and/or suppression of outflow was suggested as a cause for aneurysmal hemorrhage (“hemodynamic theory”) (2). Cebral et al. (2) presented seven aneurysms, three with postprocedural rupture and four that were treated successfully. Using computational fluid dynamics, the authors’ calculations showed that all three aneurysms that ruptured demonstrated severe increases in intra-aneurysmal pressure (>20 mm Hg) after treatment, whereas those aneurysms that did not rupture after treatment did not exhibit such dramatic pressure increases (<3 mm Hg). This pressure increase was suggested to be related to larger effective resistance in the parent artery from placement of the devices (2). The process of thrombus formation begins with the stagnation of blood flow, leading to the formation of red thrombus, progressing to a white thrombus, followed by subsequent thrombus organization. Red thrombi contain proteolytic enzymes and leucocytes. A large amount and a prolonged phase of red thrombus within the aneurysm without progression to an organized thrombus might promote an inflammatory reaction, eventually resulting in the disintegration of the aneurysm wall with subsequent rupture (“inflammatory theory”) (18, 34).
In-Stent Stenosis. With the current available short and mid-term safety data on PED, the risk of delay in-stent stenosis is relatively low with no clinical significant sequelae requiring intervention noted. Reported stenosis rates between 2.2% and 10% at 3 to 6 months’ follow-up (total of 13 reported) 9 stenoses were mild (25%50%) (11, 19, 21, 27). Using magnetic resonance angiography, Szikora et al. (33) reported no in-stent stenosis at 6 months on DSA or at 1.5 to 2 years. Without long-term data available,
however, the overall risk of in-stent stenosis remains unclear. Evidence suggests that PED is capable of treating difficult aneurysms but also provides insight into some of the challenges and areas of ambiguity with PED treatment. Further research is essential to explore the following areas of ambiguity: (1) prognostic factors for aneurysmal thrombosis and overall occlusion and whether the OKM grading scale is useful in this regard; (2) whether the use of multiple PEDs is superior in inducing aneurysm thrombosis than a single device; (3) identifying patients at risk of early post-PED placement hemorrhage and whether this can be decreased by adjunctive coil or multiple PEDs placement; (4) the long-term risk of in-stent stenosis; (5) the optimal antiplatelet loading and treatment regimen; (6) the natural history of aneurysms that fail to thrombose and obliterate at follow-up; and (7) the optimal time to declare treatment failure and the best strategies to tackle the problem. CONCLUSION PED offers an alternative to endovascular coiling for aneurysms with complex morphology. The indication for its use has evolved from giant aneurysms with wide necks to small aneurysms. The safety profile of PED is comparable with or possibly superior to balloon-remodeling or stent-assisted coil embolization in specific circumstances. However, questions remain regarding the long-term safety, treatment results, and clinical outcomes. Continued ongoing research and monitoring of the usage of PED are warranted. REFERENCES 1. Campi A, Ramzi N, Molyneux AJ, Summers PE, Kerr RS, Sneade M, Yarnold JA, Rischmiller J, Byrne JV: Retreatment of ruptured cerebral aneurysms in patients randomized by coiling or clipping in the International Subarachnoid Aneurysm Trial (ISAT). Stroke 38:1538-1544, 2007. 2. Cebral JR, Mut F, Raschi M, Scrivano E, Ceratto R, Lylyk P, Putman CM: Aneurysm rupture following treatment with flow-diverting stents: computational hemodynamics analysis of treatment. Am J Neuroradiol 32:27-33, 2011. 3. Choi DS, Kim MC, Lee SK, Willinsky RA, Terbrugge KG: Clinical and angiographic longterm follow-up of completely coiled intracranial aneurysms using endovascular technique. J Neurosurg 112:575-581, 2010.
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4. Ferns SP, Sprengers ME, van Rooij WJ, Rinkel GJ, van Rijn JC, Bipat S, Sluzewski M, Majoie CB: Coiling of intracranial aneurysms: a systematic review on initial occlusion and reopening and retreatment rates. Stroke 40:e523-e529, 2009. 5. Ferns SP, Sprengers ME, van Rooij WJ, van Zwam WH, de Kort GA, Velthuis BK, Schaafsma JD, van den Berg R, Sluzewski M, Brouwer PA, Rinkel GJ, Majoie CB: Late reopening of adequately coiled intracranial aneurysms: frequency and risk factors in 400 patients with 440 aneurysms. Stroke 42:1331-1337, 2011. 6. Fiorella D: Pipeline in clinical practice in 2011. Neuroradiology 54:277-278, 2012. 7. Fiorella D, Hsu D, Woo HH, Tarr RW, Nelson PK: Very late thrombosis of a Pipeline embolization device construct: case report. Neurosurgery 67: E313-E314, 2010. 8. Fiorella D, Kelly ME, Albuquerque FC, Nelson PK: Curative reconstruction of a giant midbasiar trunk aneurysm with the Pipeline embolization device. Neurosurgery 64:212-217, 2009. 9. Fiorella D, Lylyk P, Szikora I, Kelly ME, Albuquerque FC, McDougall CG, Nelson PK: Curative cerebrovascular reconstruction with the Pipeline embolization device: the emergence of definitive endovaswith the Pipeline embolization device: the emergence of definitive endovascular therapy for intracranial aneurysms. J Neurointerv Surg 1:56-65, 2009. 10. Fiorella D, Woo HH, Albuquerque FC, Nelson PK: Definitive reconstruction of circumferential, fusiform intracranial aneurysms with the pipeline embolization device. Neurosurg 62:1115-1121, 2008. 11. Fischer S, Vajda Z: Aguilar Perez M, Schmid E, Hopf N, Bäzner H, Henkes H: Pipeline embolization device (PED) for neurovascular reconstruction: initial experience in the treatment of 101 intracranial aneurysms and dissections. Neuroradiology 54:369-382, 2012.
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16. Kim DJ, Suh SH, Kim BM, Kim DI, Huh SK, Lee JW: Hemorrhagic complications related to the stent-remodeled coil embolization of intracranial aneurysms. Neurosurgery 67:73-78, 2010. 17. Koebbe CJ, Veznedaroglu E, Jabbour P, Rosenwasser RH: Endovascular management of intracranial aneurysms: current experience and future advances. Neurosurgery 59:S3-13, 2006. 18. Kulcsár Z, Houdart E, Bonafé A, Parker G, Millar J, Goddard AJ, Renowden S, Gál G, Turowski B, Mitchell K, Gray F, Rodriguez M, van den Berg R, Gruber A, Desal H, Wanke I, Rüfenacht DA: Intraaneurysmal thrombosis as a possible cause of delayed aneurysm rupture after flow-diversion treatment. Am J Neuroradiol 32:20-25, 2011. 19. Lubicz B, Collignon L, Raphaeli G, De Witte O: Pipeline flow-diverter stent for endovascular treatment of intracranial aneurysms: preliminary experience in 20 patients with 27 aneurysms. World Neursurg 76:114-119, 2011. 20. Lubicz B, Collignon L, Raphaeli G, Pruvo JP, Bruneau M, DeWitte O, Leclerc X: Flow-diverter stent for the endovascular treatment of intracranial aneurysms: a prospective study in 29 patients with 34 aneurysms. Stroke 41:2247-2253, 2010.
30. Raymond J, Guilbert F, Weill A, Georganos SA, Juravsky L, Lambert A, Lamoureux J, Chagnon M, Roy D: Long-term angiographic recurrences after selective endovascular treatment of aneurysms with detachable coils. Stroke 34:1398-1403, 2003. 31. Sadasivan C, Cesar L, Seong J, Wakhloo AK, Lieber BB: Treatment of rabbit elastase-induced aneurysm models by flow diverters: development of quantifiable indexes of device performance using digital subtraction angiography. IEEE Trans Med Imaging 28:1117-1125, 2009. 32. Shapiro M, Babb J, Becske T, Nelson PK: Safety and efficacy of adjunctive balloon remodeling during endovascular treatment of intracranial aneurysms: a literature review. Am J Neurol Radiol 29:1777-1781, 2008. 33. Szikora I, Berentei Z, Kulcsar Z, Marosfoi M, Vajda ZS, Lee W, Berez A, Nelson PK: Treatment of intracranial aneurysms by functional reconstruction of the parent artery: the budapest experience with the pipeline embolization device. Am J Neuroradiol 31:1139-1147, 2010.
22. Martin AR, Pablo Cruz J, Matouk CC, Md JS, Marotta TR: The Pipeline flow-diverting stent for exclusion of ruptured intracranial aneurysms with difficult morphologies. Neurosurgery 70:21-28, 2012.
34. Turowski B, Macht S, Kulcsár Z, Hänggi D, Stummer W: Early fatal hemorrhage after endovascular cerebral aneurysm treatment with a flow diverter (SILK-Stent): do we need to rethink our concepts? Neuroradiology 53:37-41, 2011.
23. McDougall CG, Spetzler RF, Zabramski JM, Partovi S, Hills NK, Nakaji P, Albuquerque FC: Barrow ruptured aneurysm trial. J Neurosurg 116: 134-144, 2012.
35. Vallee JN, Aymard A, Vicaut E, Reis M, Merland JJ: Endovascular treatment of basilar tip aneurysms with Guglielmi detachable coils: predictors of immediate and long- term results with multivariate analysis 6-year experience. Radiology 226: 867-879, 2003.
24. Molyneux A, Kerr R, Stratton I, Sandercock P, Clarke M, Shrimpton J: Holman: International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: A randomized trial. J Stroke Cerebrovasc Dis 11:304-314, 2002.
13. Gonzalez NR, Duckwiler G, Jahan R, Murayama Y, Viñuela F: Challenges in the endovascular treatment of giant intracranial aneurysms. Neurosurgy 62:S1324-S1335, 2008.
25. Murayama Y, Nien YL, Duckwiler G, Gobin YP, Jahan R, Frazee J, Martin N, Viñuela F: Guglielmi detachable coil embolization of cerebral aneurysms: 11 years’ experience. J Neurosurg 98: 955-966, 2003.
15. Kallmes DF, Ding YH, Dai D, Kadirvel R, Lewis DA, Cloft HJ: A second-generation, endoluminal, flow-disrupting device for treatment of saccular aneurysms. Am J Neuroradiol 30: 1153-1158, 2009.
29. Pierot L: Flow diverter stents in treatment of intracranial aneurysm. Where are we? J Neuroradiol 38:40-46, 2011.
21. Lylyk P, Miranda C, Ceratto R, Ferrario A, Scrivano E, Luna HR, Berez AL, Tran Q, Nelson PK, Fiorella D: Curative endovascular reconstruction of cerebral aneurysms with the Pipeline Embolization Device: The Buenos Aires experience. Neurosurgery 64:632-643, 2009.
12. Friedman JA, Nichols DA, Meyer FB, Pichelmann MA, McIver JI, Toussaint LG 3rd, Axley PL, Brown RD Jr: Guglielmi detachable coil treatment of ruptured saccular cerebral aneurysms: Retrospective review of a 10-year single center experience. Am J Neuroradiol 24:526-533, 2003.
14. Kallmes DF, Ding YH, Dai D, Kadirvel R, Lewis DA, Cloft HJ: A new endoluminal, flowdisrupting device for treatment of saccular aneurysm. Stroke 38:2346-2352, 2007.
28. O’Kelly CJ, Krings T, Fiorella D, Marotta TR: A novel grading scale for the angiographic assessment of intracranial aneurysms treated using flow diverting stents. Interv Neuroradiol 16: 133-137, 2010.
26. Narata AP, Yilmaz H, Schaller K, Lovblad KO, Pereira VM: Flow diverter stent for ruptured intracranial dissecting aneurysm of vertebral artery. Neurosurgery 70:982-989, 2012.
36. van Rooij WJ, Sluzewski M: Perforator infarction after placement of a pipeline flow diverting stent for an unruptured A1 aneurysm. Am J Neuroradiol 31:E43-E44, 2010.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 3 February 2012; accepted 27 September 2012; published online 3 October 2012 Citation: World Neurosurg. (2013) 80, 6:829-835. http://dx.doi.org/10.1016/j.wneu.2012.09.023 Journal homepage: www.WORLDNEUROSURGERY.org
27. Nelson PK, Lylyk P, Szikora I, Wetzel SG, Wanke I, Fiorella D: The pipeline embolization device for the intracranial treatment of aneurysms trial. Am J Neuroradiol 32:34-40, 2011.
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Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2013 Published by Elsevier Inc.
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Key words Intracranial aneurysms - Pipeline embolization device -
Abbreviations and Acronyms DSA: Digital Subtraction Angiography OKM: O’KellyeMarotta PED: Pipeline embolization device 1
From the Neurointervention Service, Department of Radiology, and 2Comprehensive Stroke Centre, Royal Melbourne Hospital, Melbourne, Victoria; and 3Melbourne Brain Centre, University of Melbourne, Parkville, Melbourne, Victoria, Australia To whom correspondence should be addressed: Mona M.Y. Tse, M.B.B.S., F.H.K.C.P. [E-mail: [email protected]] Citation: World Neurosurg. (2013) 80, 6:829-835. http://dx.doi.org/10.1016/j.wneu.2012.09.023 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2013 Published by Elsevier Inc.
INTRODUCTION The treatment of endovascular aneurysm has evolved considerably during the past two decades, with coiling emerging as the treatment of choice for a significant proportion of saccular aneurysms (17). The International Study of Subarachnoid Aneurysm Treatment (24) and the Barrow Ruptured Aneurysm Trial (23) have established the advantages of endovascular treatment in selected clinical scenarios. However, a considerable number of aneurysms are not amendable to coiling. Balloon remodeling and stent-assisted techniques were developed in mid-1990s and early 2000, rendering more feasible the treatment of aneurysms with more complex morphology (17). Despite the technological advances, wide-neck and giant saccular or fusiform aneurysms present considerable challenges for the operator (13). Parent artery occlusion is one of the earliest endovascular techniques that showed efficacy treatment for unclippable giant aneurysms. However, parent artery occlusion depends on patient tolerance to occlusion,
- OBJECTIVE:
Pipeline embolization device (PED) implantation is a novel endovascular treatment option for the treatment of intracranial aneurysms. It is emerging as a useful alternative to coiling and to open surgery, and its use is increasing worldwide. We performed a literature review to examine its efficacy, technical challenges, and safety.
- METHODS:
PubMed database was used to identify all articles relating to PED.
- RESULTS:
The review outlines the indications for PED, its technical aspects, complications, and clinical outcomes.
- CONCLUSIONS:
PED offers an alternative to endovascular coiling for aneurysms with complex morphology. The indication for its use has evolved from the limited scope of treatment of giant aneurysms with wide necks to the inclusion of smaller aneurysms. The procedural safety profile of PED is comparable with or possibly superior to balloon-remodeling or stent-assisted coil embolization in specific circumstances. However, questions remain regarding the incidence of post-procedural subarachnoid hemorrhage. Ongoing monitoring and meticulous documentation of PED postimplantation safety is strongly recommended.
and reliable predictors for ischemic events are lacking. (13) Furthermore, successful balloon occlusion test does not preclude delayed ischemic complications that occur between 4% and 15% of cases. (13) Endovascular treatments frequently fail to produce complete occlusion in such aneurysms (1). Recurrence of the treated aneurysm postendovascular treatment occurs in 9% to 34% cases (1, 3-5, 25, 30). Incomplete occlusion, larger (>10 mm) aneurysm size, and neck size are risk factors for recurrence (1, 3-5, 25, 30). These aneurysms are prone to coil compaction and recanalization, even when complete or near-complete occlusion has been achieved after the initial embolization, and require extended imaging surveillance and the possibility of retreatment (12, 24, 25, 35). Failure of endovascular techniques to achieve a complete and durable occlusion of aneurysms has been attributed to several factors, including limitations with respect to the volumetric packing of the aneurysm sac with coils, inherent difficulties associated with achieving a continuous reconstruction of large complex aneurysm neck
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defects with coils, and finally a fundamental failure of the endovascular strategy to address the underlying diseased parent vessel (9). MATERIALS AND METHODS Literature Review A search for published articles on pipeline embolization devices (PED) in PubMed between 2000 and February 2012 was performed. A total of 210 patients with 241 aneurysms treated with PED were identified in five reported case series. A detail review on the indications, therapeutic results, and technical and safety issues of PED was performed. Principle of Flow Diversion Flow diversion offers a fundamentally novel treatment approach. This approach potentially represents a more physiologic treatment of intracranial aneurysms in comparison with coil embolization. Flow-diversion devices produce both haemodynamic and biological effects, namely (1) flow redirection promoting flow stasis
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and thrombosis in the aneurysm and (2) tissue overgrowth where the stent provides a scaffolding for the development of endothelial and neointimal tissue across the aneurysmal neck (29). By redirecting blood flow along the normal course of the parent artery, flow-diversion devices markedly alter dynamic fluid exchange across the aneurysm/ parent vessel interface, creating an intra-aneurysmal environment that is conducive to thrombosis (14, 15, 31). After successful aneurysm thrombosis, the construct becomes progressively incorporated into the parent artery through a process of neointimal overgrowth, and a continuous, homogeneous layer of tissue unites the normal parent artery segments proximal and distal to the aneurysm neck defect, completing the process of endoluminal reconstruction (14, 15, 31). This step ultimately results in the anatomic exclusion of the aneurysm from the circulation and promotes final involution of the aneurysmal mass as the intrasaccular thrombus is resorbed. PED PED (ev3, Irvine, California, USA) is a flexible self-expanding, microcatheter-delivered, high-metal-surface-area coverage, stent-like device designed to achieve aneurysm occlusion through the endoluminal reconstruction of the diseased segment of the parent artery that gives rise to the aneurysm (Figure 1). Composed of 48 individual cobalt chromium and platinum strands, it provides 30% to 35% metal surface area coverage when fully deployed (10), in comparison with only 6% to 9.5% coverage with conventional bare metal stents (e.g., Neuroform stent; Boston
Figure 1. Pipeline embolization device (Ev3, Irvine, California, USA).
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Scientific/Target Therapeutics, Fremont, California, USA) and 12% to 16% with balloon-mounted stents (21). Devices are available with a nominal diameter from 2.5 to 5 mm with 0.25-mm increments. The nominal length of the implants is in the range from 10 to 35 mm in 2-mm increments. At the nominal diameter, the pore size is 0.02 to 0.05 mm2, and the radial force is approximately 2.0 mN/mm (3.0 mm vessel diameter). PED is premounted on a stainless-steel wire with a radiopaque 15-mm platinum tip extends beyond the end of the PED and is delivered via a 0.027-inch ID microcatheter. PED has received the Conformité Européene mark of approval on the basis of the Pipeline Embolization Device for the Intracranial Treatment of Aneurysms (PITA) trial (27) and has been sold outside the United States since July 2009. On the basis of the results of the Pipeline for Uncoilable or Failed Aneurysms (PUFS) clinical study that included safety and efficacy data on 108 patients, in April 2012, PED received premarket approval from the U.S. Food and Administration for the endovascular treatment of adults (>22 years of age) with large or giant, widenecked intracranial aneurysms of the internal carotid artery from the petrous to the superior hypophyseal segments. Compassionate use of PED is allowed in patients who meet the criteria for treatment but do not qualify for the inclusion criteria in PUFS study because of their age or the location of the aneurysm and for whom there are no other reasonable alternative treatments.
RESULTS Aneurysm Selection and Limitations With larger patient series being published recently, confirming the efficacy of the device and its safety profile, the use of PED has transformed during the past few years from a novel, investigational device reserved for otherwise-untreatable lesions to a more established alternative technique that is being integrated into routine cerebrovascular practice (6). A transition in the use of PED in treating large and giant aneurysms to include small- to mediumsized aneurysms has been observed. Large to giant, broad-necked aneurysms comprised the majority of aneurysms
treated in previous studies. In these studies, mean diameter and neck size of treated aneurysms was between 11.1 to 16 mm and 5.8 to 7.4 mm, respectively (21, 27, 33); 48% to 73.3% of these aneurysms were greater than 10 mm compared with mean aneurysm sizes of 3.8 to 5.13 in later studies (Table 1) (11, 19). In more recent studies, small- to medium-sized aneurysms were the target aneurysm size. Lubicz et al. (19) and Fischer et al. (11) each recruited patients with aneurysms greater than 10 mm in only 11.1% and 2.9%, respectively, with 59% and 48.5%, respectively, less than 5 mm. Forty-four to 66% were recurring aneurysms (Table 1) (11, 19). The differences in these aforementioned studies highlight a gradual transition of PED from being an investigational device in treating large and giant aneurysms to a standard treatment options for recurring or de novo aneurysms in the size range encountered more commonly in clinical practice. Very small or blister aneurysms (<2 mm) pose a different challenge for conventional endovascular coiling because both catheterization and the need of endovascular coil placement have increased risk of procedural rupture, especially in curved vessels. Martin et al. (22) reported a patient with aneurysms smaller than 2 mm who presented with acute subarachnoid hemorrhage and was successfully treated with PED. PED may offer an attractive alternative method in treating these patients with very small or blister aneurysms, potentially reducing risk of periprocedural rupture. Despite the fact the size range of aneurysms treated with PED has increased dramatically during the past 2 years, the clinical indications remains largely unchanged, that is, (1) for wide neck aneurysms with high likelihood of failure with conventional endovascular therapy or microsurgery; (2) to treat remnants of aneurysms after clips and coiling treatment; (3) fusiform aneurysms; and (4) dissecting aneurysms. PED has two major limitations in its application. First, because it originally was designed for sidewall aneurysms, its use in bifurcation aneurysms has been limited. The potential use with a “kissing” implantation of two PEDs or in combination with conventional stents to create a bidirectional flow diversions has not been fully evaluated. Second, the associated delayed aneurysm
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Table 1. Summary of Aneurysms Characteristics Treated with PED Across Various Studies Authors
Lylyk et al., 2009 (21)
Szikora et al., 2010 (33)
Journal
Neurosurgery 2009
American Journal of Neuroradiology
Number of patients/ aneurysms
53/63
18/19
Morphology
33 (<10 mm)
5 (<10 mm)
20 (<10 mm)
13 (<5 mm)
49 (<5 mm)
22 (1025 mm)
10 (1025 mm)
9 (1025 mm)
11 (510 mm
11 (510 mm)
8 (>25 mm)
4 (>25 mm)
2 (>25 mm)
3 (>10 mm)
3 (>10 mm)
Mean size 5.13 mm 13/20 (65%) has wide neck
Mean size 3.8 mm (215 mm) Neck 3.3 mm (215 mm)
12 (44.4)
54 (53)
Mean size 11.1 mm (3.530 mm) Neck size >4 mm in 100% of cases Recurrence, n (%)
23 (37)
thrombosis and the need for dual antiplatelet after treatment makes PED unsuitable for ruptured aneurysms in acute phase. The use of PED treating ruptured dissecting or blister aneurysms in acute situation, however, has been reported in recent two case reports (22, 26). Technical Challenges PED differs from other intracranial stents, such as Neuroform (Boston Scientific/ Target Therapeutics) or Wingspan (Boston Scientific/Target Therapeutics) in some aspects, presenting several distinct technical challenges in clinical practice. First, the delivery catheter must recross the Pipeline device over the delivery wire to recapture the distal coil tip after complete stent deployment. Second, significant foreshortening is noted in PED. Up to 50% foreshortening is expected when fully deployed compared with 1.5% to 7.1% and 1.8% to 5.4% foreshortening in Wingspan and Neuroform stents, respectively. The longest available length of the device is 35 mm, which makes reconstruction with telescoping PEDs necessary to cover the entire length of large fusiform or dissecting aneurysms. This potentially increases the risk of arterial branch or perforator occlusion in the overlapped segment. Special attention to these distinctive features of PED is essential to enable successful PED deployment and placement. Device Deployment. Device deployment is successful consistently in 87% to 100% across many studies (11, 19, 21, 27, 33).
Mean size 16 mm Mean neck size 7.4 mm (418 mm) 1 (5.3)
Nelson et al., 2011 (27) American Journal of Neuroradiology 31/31
Mean size 11.5 mm Mean neck size 5.8 mm 71% neck >4 mm 12 (38.7)
Earlier studies have slightly lower success rates of 87% to 97% (21, 27, 33) in contrast to near 100% (99%100%) in more recent series (11, 19). This difference likely reflects technical improvement over time. There were a total of eight PED deployment failures reported in two series. All of these were encountered when PED was deployed across very tortuous vessels, which created excessive friction (27, 33). Problems in recapturing the distal coil tip of the delivery wire are not uncommon. Lylyk et al (21) reported one (1.5%) case where the distal coil tip fractured and became engaged in the deployed PED. Lubicz et al. (19) reported seven (25%) other failures to recapture the distal coil tip. Selection of Device Diameter and Length. Selection of the appropriate diameter and length of the device is essential to ensure proper stent function and to minimize the chance for unanticipated stent shortening or migration. Allowance for the anticipated foreshortening of approximately 50%, and possible device shift during deployment is critical when choosing the length of the device (20). There is a potential risk of an endoleak-like phenomenon with implantation of an undersized device, which results in poor wall apposition. Similarly, implantation of an oversized device may result in poor coverage of the lesion because of an incomplete compaction of the strands (11). These problems can affect the overall efficacy of PED. The diameter of the proximal segment of the target vessel and the
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Fischer et al., 2012 (11)
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diameter at the origin of the lesion determine the diameter of the PED (11). The distal vessel diameter is of lesser importance. Selection of a stent diameter 0.25 to 0.5 mm larger than the distal parent diameter is also recommended (19). The presence of existing conventional stents may complicate the delivery and deployment of PED. Fischer et al. (11) reported a greater periprocedural complication rate compared with those patients without a pre-existing stents (2% vs. 13%). Overall, the technical complications occurred in range of 3.1% to 33.3% depending upon the definition of technical complications in different studies. Most of these complications did not result in clinical significant sequelae. Angiographic Evaluation of Aneurysms After Flow Diversion Treatment. No standardized postprocedural angiographic evaluation after flow diversion placement was used in earlier studies. Lylyk et al. (21) used an “all-or-none” assessment (i.e., aneurysm fills or not) whereas Nelson et al. (27) used the three-point Raymond scale to assess the aneurysm status postflow diversion treatment. Specific periprocedural angiographic assessment postflow diverter stent placement was first described by Szikora et al. (33) and was further elaborated by O’Kelly et al. (28), who developed the O’KellyeMarotta (OKM) grading scale in 2010 aiming to facilitate communication and standardize outcomes assessment after flow diversion treatment. This scale takes into account the amount of
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aneurysm perfusion and stasis of contrast medium. Aneurysm perfusion is graded as: A, complete perfusion (>95%); B, incomplete perfusion (5%e95%); C, neck remnant (>5%); or D, no perfusion (0%). The contrast medium stagnation grade is determined by the timing of contrast medium clearance from the aneurysm sac as defined by the phases of the angiogram: 1, no stasis (clearance within the arterial phase); 2, moderate stasis (clearance before the venous phase); 3, significant stasis (contrast persists in the aneurysm into the venous phase and beyond). This scale was used in two studies in 2011 (11, 19). The duration of contrast stasis induced by a flow diverter might be a helpful tool to estimate the likelihood of complete intraaneurysmal thrombosis (28). This might also help to determine the need for more than one flow diverter during the procedure. Fischer et al. (11) indeed decided the need for more than one PED in their patients depending on the OKM grading scale. Although additional coiling did not alter the overall aneurysm thrombosis rate (33), whether the use of additional PEDs (which created a greater contrast stagnation score), translates into earlier aneurysm thrombosis and overall greater obliteration rate needs further research. Efficacy of PED Prediction of Aneurysm Occlusion. The primary aim of flow diversion treatment of an aneurysm is to induce a process of intraaneurysmal thrombus formation, with the final goal of complete aneurysm occlusion. This usually occurs between a few months and a year. Residual or even unchanged intra-aneurysmal contrast filling is an expected finding immediately after PED placement in the majority of cases, whereas immediate aneurysm exclusion is considered an uncommon occurrence. It may be presumed that aneurysm size and geometry or the total number of PEDs placed across the aneurysms neck may play a role in predicting time to aneurysmal thrombosis. In fact, immediate aneurysm exclusion has been reported by Lylyk et al. (21) and Szikora et al. (33) with 8% and 21% (3 with additional coiling), respectively, of aneurysms less than 5 mm respectively occluding immediately. In contrast to these earlier findings, Fischer et al. (11) reported no immediate
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aneurysm occlusion, despite the fact that 48% of the intracranial aneurysms were <5 mm and greater than 60% of the 101 aneurysms had multiple PEDs placed. This apparent discrepancy may be explained by the following: (1) more aggressive antiplatelet loading in Fischer group with aspirin 500 mg plus 600 mg of clopidogrel at least one day before procedure (11) compared with 100 to 325 mg of aspirin plus 75 mg of clopidogrel 48 to 72 hours before in other studies; (2) the geometry of the aneurysm may be a more important determining factor than size; and (3) the heterogeneity and small sample size in all the studies made meaningful statistic analysis difficult. To date, there are no identifiable procedural techniques or aneurysmal characteristics that reliably predict earlier aneurysm thrombosis and higher exclusion rates. Aneurysm Occlusion Rate. The overall aneurysms occlusion rate has been very promising, with more than 50% (range, 52%56%) at 3 months, around 90% (84%94%) at 6 months and greater than 95% at 12 months (95%100%; Figure 2). Occlusion rates of 56%, 93%, and 95% at 3, 6, and 12 months were reported by Lylyk et al. (21). Szikora et al. (33), Nelson et al. (27), and Lubicz et al. (19) reported complete occlusion rates of 94%, 93.3%, and 84% by 6 months. A total of 100% occlusion at 12 months was achieved in Nelson et al.’s group (22). Fischer et al. (11) have the lowest reported complete occlusion rate of 74% at 10 months but a comparable occlusion rate of 52% at 3 months, despite the fact that the group
had just less than half of the aneurysms under 5 mm and used multiple PEDs more than 60% of the time. The observed differences may be attributed to the extended period of dual antiplatelet therapy of 1 year compared with 6 weeks in Szikora et al.’s group (33), 1 month in Nelson et al.’s group (27), 3 to 6 months in Lubicz’s et al. (6 months if side branch was covered) (19), and 6 months in Lylyk et al.’s group (21). Prolonged dual antiplatelet treatment may significantly delay aneurysmal thrombosis. The obliteration rate of greater than 90% at 6 months achieved by PED compares favorably to endovascular coil embolization, where the highest reported complete occlusion rate was 66% in the International Subarachnoid Aneurysm Trial (24). This finding was despite the ISAT comprised aneurysms selected as suitable for coil embolization, with more than 90% small aneurysms (24). These rates of occlusion are even lower in selected subgroups such as large, giant, wide-necked, and nonsaccular aneurysms. Raymond et al. (30) also found that up to 34% of intracranial aneurysms treated with coiling recur at a mean of 12 months. Recurrence after successful PED treatment has not been reported with the available short- and medium-term data to date. Persisted or unchanged aneurysm perfusion at follow-up angiography poses a completely different and unique challenge with flow diversion treatment. Only one study addresses this issue and described the use of second PED treatment in this situation. Retreatment was performed in 8 (9%) patients with
Figure 2. Overall reported aneurysms occlusion rate versus time.
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persistent or unchanged aneurysm perfusion; final results of these patients, however, were not available (11). At present the decision to observe or to retreat these aneurysms is controversial. No evidence is currently available to guide the best treatment strategies. The additional use of coils in large or acutely ruptured aneurysms with the intention of inducing early intrasaccular thrombosis when the flow diversion effect by PED alone was thought insufficient and was not found to be associated with increased aneurysm occlusion rate (33). The two groups differ in the use of a single PED in the coil group, with multiple overlapping devices reported when PED was used alone. Lubicz et al. (19) advocate the use of additional coiling only in aneurysms with high risk of rupture or to restrict Pipeline coverage to a single device in order to minimize the risk of side branch occlusion. The presence of a previously deployed stent may reduce the hemodynamic effect of a PED (21), but Fischer et al. (11) found the occlusion rate was similar (65% vs. 69%) regardless of the presence of preexisting conventional stent. On the other hand, delayed endothelialization may be expected under these circumstances. An extended phase or lifetime-long dual platelet medication is advocated (11). Safety Aspects Current evidence supports PED as a safe device associated with low morbidity and mortality. There have been a total of 210 patients with 17 (8.1%) complications and 4 (1.9%) deaths reported. Procedural morbidity and mortality range between 4.5% and 16.6% and 0% and 5.5%, respectively. These figures are comparable with the risks of unruptured aneurysms treated by coiling. In a series of 246 patients with unruptured aneurysms treated with Guglielmi detachable coils, Murayama et al. (25) reported a 5.3% rate (13 of 246) of procedural morbidity and mortality in a group largely composed of aneurysms amenable to coiling alone. Balloon-remodeled or stent-assisted coil embolization is usually necessary in the population of aneurysms treated with PED. In a review article, Shapiro et al. (32) examined the safety of balloon-assisted or balloon remodeling coiling. They found that 443 balloon-assisted or balloon-remodeled coiled aneurysms demonstrated a morbidity
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Table 2. Reported Clinically Significant Complications, Morbidity, and Mortality Associated with Pipeline Embolization Device Treatment Across Various Studies
Complications
Lylyk et al., 2009 (21)
Szikora et al., 2010 (33)
Nelson et al., 2011 (27)
Lubicz et al., 2011 (19)
Fischer et al., 2012 (11)
Total
Mass effect
3
0
0
0
0
3
In-stent thrombosis
0
1
0
1*
2y
3
Perforator occlusion
0
0
1
0
0
1
Thromboemoblic event
0
2
0
0
0
2
Intracranial Hemorrhage
0
1y
1
2y
4y
8
3 (5)
3 (16.6)
2 (6.4)
1 (5)
4 (4.5)
13 (5.7)
Morbidity, n (%) Mortality, n (%) Morbidity and Mortality, n (%)
0
1 (5.5)
0
1 (5)
2 (2.2)
4 (1.9)
3 (5)
4 (22.2)
2 (6.4)
2 (10)
6 (6.8)
17 (8.1)
*Same patient with more than one complication. yMortality case.
and mortality of 8.1% and 1.7%, respectively, which is comparable with PED. The details of complications are outlined in Table 2. In-Stent Thrombosis. In-stent thrombosis has been reported in three patients. One occurred acutely in a patient who omitted antiplatelet before the procedure (33). Another occurred at day 5 after dual antiplatelet therapy was stopped as a result of intracerebral hemorrhage secondary to vessel wall perforation during the procedure (19). Thrombosis occurred in another patient with two telescoping PEDs placed in a pre-existing conventional stent (11). Delayed in-stent thrombosis has been reported in two patients. One occurred at 63 days after a relative short duration of dual antiplatelet therapy of 6 weeks, and resulted in death (11). Another occurred at 23 months after initial treatment with three PEDs and additional coiling, despite 6 months of dual antiplatelet followed by 12 months of high-dose (150 mg) clopidogrel (7). Currently, there are no standard guidelines or recommendations on duration and dosage of antiplatelet therapy to best prevent acute and delayed in-stent thrombosis. Dual antiplatelet agents loading before procedure and continued for a minimum of 3 months (up to 1 year in selected cases) is essential to prevent instent thrombosis. The use of prolonged dual antiplatelet therapy, however, must be balanced against the risk of delayed or
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incomplete aneurysm thrombosis and obliteration and intracranial or peripheral hemorrhage. Multiple PEDs placement appears to increase the risk of in-stent thrombosis; however, the optimal duration and regimen of antiplatelet in these situations remained to be determined. Side Branch or Perforator Occlusion. Side branch or perforator occlusion was an initial concern with multiple PEDs used in treating fusiform or dissecting aneurysms. The clinical consequences of artery occlusion are variable, with greatest risk of poor outcome likely after perforator artery occlusion. Immediate ophthalmic artery occlusion was observed after PED placement, and delayed ophthalmic artery occlusion was noted in two patients at reassessment digital subtraction angiography (DSA) at 6 months who were treated with two to four PEDs (33). Side branch occlusion at follow-up DSA was noted by Lubicz et al. (19). None of these resulted in clinical significant adverse events. Perforator occlusions seem to behave differently and are more prone to result in clinical ischaemic insult. Nelson et al. (27) reported a left basal ganglion infarct secondary to two PEDs placed in M1 segment of left middle cerebral artery with pre-existing Neuroform stent. Rooij reported another case of left basal ganglion infarction after placement of 2 telescoping PEDs in A1 segment of anterior cerebral artery (36). Both cases were thought to be
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related to occlusion of lenticulostriate arteries from M1 and A1 segments of middle cerebral artery and anterior cerebral artery, respectively. These reported cases raise the concern of using more than one PED in segments of vessels with perforators. Nelson et al. (27) recommend the overlapping of multiple PEDs in regions giving rise to eloquent perforators should be avoided. Multiple PEDs have been used to reconstruct vessels without clinical complication in other studies, with between 30-66% of aneurysms treated with multiple PEDs. No branch occlusion was observed in cases reported by Fiorella and Fischer et al (8, 11), both using 7 and 16 PEDs to reconstruct basilar trunk aneurysms respectively, with 4 to 5 complete layers of PEDs over the entire aneurysm length in one case (11). The observed discrepancy may be explained by the differences in the presence of background perforators compromised by atherosclerosis associated fusiform aneurysms compared to more conventional saccular aneurysms. Rooij and Sluzewski (36) reported the complication in a 68year-old woman in contrast to a 13-yearold girl in the case reported by Fiorella et al. (8). Intracranial Hemorrhage. Reported risk of hemorrhage after treatment with PED is relatively low (3.8%, 8 in 210 patients) but not uncommon. It is lower than all reported ischaemic events from all etiologies (4.3%). There were seven subacute intracranial hemorrhages occurring within hours to days after the procedure. They were secondary to the following: (1) rupture of a distal unprotected aneurysm in one (33); (2) parent vessel rupture in two (19, 27); (3) ipsilateral parenchymal hemorrhage in two (one patient had platelet dysfunction) (11,19); (4) from an aneurysm treated with coil and three PEDs at day 3 in one patient (11); and (5) perimesencephalic subarachnoid hemorrhage in one (19). Delayed hemorrhage was reported in one patient at 14 months after PED and 1 day after coiling occlusion of right V4 segment of vertebral artery for recurrent basilar trunk aneurysm (11). The reported hemorrhage rate is similar to conventional stent-assisted coiling embolization in unruptured aneurysms (3%) reported by Kim et al. (16). Kim et al.
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proposed the hemorrhagic transformation in the recently infarcted brain is the cause for the parenchymal hemorrhage. This may explain the two ipsilateral parenchymal hemorrhages encountered. The underlying cause for index aneurysmal rupture after flow diversion therapy is unclear at the moment. Two mechanisms have been proposed, the hemodynamic and inflammatory theory. An unfavorable valve mechanism with augmentation of inflow and/or suppression of outflow was suggested as a cause for aneurysmal hemorrhage (“hemodynamic theory”) (2). Cebral et al. (2) presented seven aneurysms, three with postprocedural rupture and four that were treated successfully. Using computational fluid dynamics, the authors’ calculations showed that all three aneurysms that ruptured demonstrated severe increases in intra-aneurysmal pressure (>20 mm Hg) after treatment, whereas those aneurysms that did not rupture after treatment did not exhibit such dramatic pressure increases (<3 mm Hg). This pressure increase was suggested to be related to larger effective resistance in the parent artery from placement of the devices (2). The process of thrombus formation begins with the stagnation of blood flow, leading to the formation of red thrombus, progressing to a white thrombus, followed by subsequent thrombus organization. Red thrombi contain proteolytic enzymes and leucocytes. A large amount and a prolonged phase of red thrombus within the aneurysm without progression to an organized thrombus might promote an inflammatory reaction, eventually resulting in the disintegration of the aneurysm wall with subsequent rupture (“inflammatory theory”) (18, 34).
In-Stent Stenosis. With the current available short and mid-term safety data on PED, the risk of delay in-stent stenosis is relatively low with no clinical significant sequelae requiring intervention noted. Reported stenosis rates between 2.2% and 10% at 3 to 6 months’ follow-up (total of 13 reported) 9 stenoses were mild (25%50%) (11, 19, 21, 27). Using magnetic resonance angiography, Szikora et al. (33) reported no in-stent stenosis at 6 months on DSA or at 1.5 to 2 years. Without long-term data available,
however, the overall risk of in-stent stenosis remains unclear. Evidence suggests that PED is capable of treating difficult aneurysms but also provides insight into some of the challenges and areas of ambiguity with PED treatment. Further research is essential to explore the following areas of ambiguity: (1) prognostic factors for aneurysmal thrombosis and overall occlusion and whether the OKM grading scale is useful in this regard; (2) whether the use of multiple PEDs is superior in inducing aneurysm thrombosis than a single device; (3) identifying patients at risk of early post-PED placement hemorrhage and whether this can be decreased by adjunctive coil or multiple PEDs placement; (4) the long-term risk of in-stent stenosis; (5) the optimal antiplatelet loading and treatment regimen; (6) the natural history of aneurysms that fail to thrombose and obliterate at follow-up; and (7) the optimal time to declare treatment failure and the best strategies to tackle the problem. CONCLUSION PED offers an alternative to endovascular coiling for aneurysms with complex morphology. The indication for its use has evolved from giant aneurysms with wide necks to small aneurysms. The safety profile of PED is comparable with or possibly superior to balloon-remodeling or stent-assisted coil embolization in specific circumstances. However, questions remain regarding the long-term safety, treatment results, and clinical outcomes. Continued ongoing research and monitoring of the usage of PED are warranted. REFERENCES 1. Campi A, Ramzi N, Molyneux AJ, Summers PE, Kerr RS, Sneade M, Yarnold JA, Rischmiller J, Byrne JV: Retreatment of ruptured cerebral aneurysms in patients randomized by coiling or clipping in the International Subarachnoid Aneurysm Trial (ISAT). Stroke 38:1538-1544, 2007. 2. Cebral JR, Mut F, Raschi M, Scrivano E, Ceratto R, Lylyk P, Putman CM: Aneurysm rupture following treatment with flow-diverting stents: computational hemodynamics analysis of treatment. Am J Neuroradiol 32:27-33, 2011. 3. Choi DS, Kim MC, Lee SK, Willinsky RA, Terbrugge KG: Clinical and angiographic longterm follow-up of completely coiled intracranial aneurysms using endovascular technique. J Neurosurg 112:575-581, 2010.
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16. Kim DJ, Suh SH, Kim BM, Kim DI, Huh SK, Lee JW: Hemorrhagic complications related to the stent-remodeled coil embolization of intracranial aneurysms. Neurosurgery 67:73-78, 2010. 17. Koebbe CJ, Veznedaroglu E, Jabbour P, Rosenwasser RH: Endovascular management of intracranial aneurysms: current experience and future advances. Neurosurgery 59:S3-13, 2006. 18. Kulcsár Z, Houdart E, Bonafé A, Parker G, Millar J, Goddard AJ, Renowden S, Gál G, Turowski B, Mitchell K, Gray F, Rodriguez M, van den Berg R, Gruber A, Desal H, Wanke I, Rüfenacht DA: Intraaneurysmal thrombosis as a possible cause of delayed aneurysm rupture after flow-diversion treatment. Am J Neuroradiol 32:20-25, 2011. 19. Lubicz B, Collignon L, Raphaeli G, De Witte O: Pipeline flow-diverter stent for endovascular treatment of intracranial aneurysms: preliminary experience in 20 patients with 27 aneurysms. World Neursurg 76:114-119, 2011. 20. Lubicz B, Collignon L, Raphaeli G, Pruvo JP, Bruneau M, DeWitte O, Leclerc X: Flow-diverter stent for the endovascular treatment of intracranial aneurysms: a prospective study in 29 patients with 34 aneurysms. Stroke 41:2247-2253, 2010.
30. Raymond J, Guilbert F, Weill A, Georganos SA, Juravsky L, Lambert A, Lamoureux J, Chagnon M, Roy D: Long-term angiographic recurrences after selective endovascular treatment of aneurysms with detachable coils. Stroke 34:1398-1403, 2003. 31. Sadasivan C, Cesar L, Seong J, Wakhloo AK, Lieber BB: Treatment of rabbit elastase-induced aneurysm models by flow diverters: development of quantifiable indexes of device performance using digital subtraction angiography. IEEE Trans Med Imaging 28:1117-1125, 2009. 32. Shapiro M, Babb J, Becske T, Nelson PK: Safety and efficacy of adjunctive balloon remodeling during endovascular treatment of intracranial aneurysms: a literature review. Am J Neurol Radiol 29:1777-1781, 2008. 33. Szikora I, Berentei Z, Kulcsar Z, Marosfoi M, Vajda ZS, Lee W, Berez A, Nelson PK: Treatment of intracranial aneurysms by functional reconstruction of the parent artery: the budapest experience with the pipeline embolization device. Am J Neuroradiol 31:1139-1147, 2010.
22. Martin AR, Pablo Cruz J, Matouk CC, Md JS, Marotta TR: The Pipeline flow-diverting stent for exclusion of ruptured intracranial aneurysms with difficult morphologies. Neurosurgery 70:21-28, 2012.
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23. McDougall CG, Spetzler RF, Zabramski JM, Partovi S, Hills NK, Nakaji P, Albuquerque FC: Barrow ruptured aneurysm trial. J Neurosurg 116: 134-144, 2012.
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24. Molyneux A, Kerr R, Stratton I, Sandercock P, Clarke M, Shrimpton J: Holman: International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: A randomized trial. J Stroke Cerebrovasc Dis 11:304-314, 2002.
13. Gonzalez NR, Duckwiler G, Jahan R, Murayama Y, Viñuela F: Challenges in the endovascular treatment of giant intracranial aneurysms. Neurosurgy 62:S1324-S1335, 2008.
25. Murayama Y, Nien YL, Duckwiler G, Gobin YP, Jahan R, Frazee J, Martin N, Viñuela F: Guglielmi detachable coil embolization of cerebral aneurysms: 11 years’ experience. J Neurosurg 98: 955-966, 2003.
15. Kallmes DF, Ding YH, Dai D, Kadirvel R, Lewis DA, Cloft HJ: A second-generation, endoluminal, flow-disrupting device for treatment of saccular aneurysms. Am J Neuroradiol 30: 1153-1158, 2009.
29. Pierot L: Flow diverter stents in treatment of intracranial aneurysm. Where are we? J Neuroradiol 38:40-46, 2011.
21. Lylyk P, Miranda C, Ceratto R, Ferrario A, Scrivano E, Luna HR, Berez AL, Tran Q, Nelson PK, Fiorella D: Curative endovascular reconstruction of cerebral aneurysms with the Pipeline Embolization Device: The Buenos Aires experience. Neurosurgery 64:632-643, 2009.
12. Friedman JA, Nichols DA, Meyer FB, Pichelmann MA, McIver JI, Toussaint LG 3rd, Axley PL, Brown RD Jr: Guglielmi detachable coil treatment of ruptured saccular cerebral aneurysms: Retrospective review of a 10-year single center experience. Am J Neuroradiol 24:526-533, 2003.
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28. O’Kelly CJ, Krings T, Fiorella D, Marotta TR: A novel grading scale for the angiographic assessment of intracranial aneurysms treated using flow diverting stents. Interv Neuroradiol 16: 133-137, 2010.
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36. van Rooij WJ, Sluzewski M: Perforator infarction after placement of a pipeline flow diverting stent for an unruptured A1 aneurysm. Am J Neuroradiol 31:E43-E44, 2010.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 3 February 2012; accepted 27 September 2012; published online 3 October 2012 Citation: World Neurosurg. (2013) 80, 6:829-835. http://dx.doi.org/10.1016/j.wneu.2012.09.023 Journal homepage: www.WORLDNEUROSURGERY.org
27. Nelson PK, Lylyk P, Szikora I, Wetzel SG, Wanke I, Fiorella D: The pipeline embolization device for the intracranial treatment of aneurysms trial. Am J Neuroradiol 32:34-40, 2011.
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