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Endovascular strategy for unruptured cerebral aneurysms
European Journal of Radiology 82 (2013) 1638–1645
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European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Endovascular strategy for unruptured cerebral aneurysms S. Mangiafico a , G. Guarnieri b,∗ , A. Consoli a , G. Ambrosanio b , M. Muto b a b
Interventional Neuroradiology Unit, Careggi University Hospital, Florence, Italy Neuroradiology Service, Cardarelli Hospital, Naples, Italy
a r t i c l e
i n f o
Article history: Received 1 November 2012 Accepted 2 November 2012 Keywords: Unruptured intracranial aneurysms Wall-side aneurysms Bifurcational aneurysms “H-shape” aneurysms Flow-diverter stenting Y-stenting Recanalization cerebral aneurysm Cerebral aneursysm Endovascular treatment Angiography
a b s t r a c t The treatment of unruptured intracranial aneurysms (UIAs) remains complex and not clearly defined. While for ruptured intracranial aneurysms the management and the treatment option (surgery or endovascular treatment) are well defined by several trials, for asymptomatic UIAs the best management is still currently uncertain. The rationale to treat an UIA is to prevent the rupture and its consequent SAH and all complications derived from hemorrhage or reduce/eliminate neurological palsy. Although this statement is correct, the indication to treat an UIA should be based on a correct balance between the natural history of UIA and treatment risk. Patient’s clinical history, aneurysm characteristics, and strategy management influence the natural history of UIAs and treatment outcomes. In the last 10 years and more, two important large multicenter studies were performed in order to analysis of all these factors and to evaluate the best treatment option for UIAs. The aim of this paper is to try to synthesize the possible indications to the endovascular treatment (EVT), when and how to treat an UIA. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The treatment of unruptured intracranial aneurysms (UIAs) remains complex and not clearly defined. While for ruptured intracranial aneurysms the management and the treatment option (surgery or endovascular treatment) are well defined by several trials [1,2]; for asymptomatic UIAs the best management is still currently uncertain. The prevalence of UIAs is estimated at 2–4% of the adult population with an incidence of subarachnoid hemorrhage (SAH) due to their rupture at 10/100,000/year [3]. High morbidity and mortality (45–75%) rate due to SAH are very well known and described, despite the current technique of treatment and reanimation assistance [4]. Despite the fact generally intracranial aneurisms are asymptomatics up to their rupture, they can have an unspecific symptom as frequent headache resistant to medical treatment or they can be disclosed by nerve palsy or compression effect to nervous structures. Thanks to the great development of mini-invasive imaging techniques in the last 20 years with CTA or MRA, the incidence
∗ Corresponding author at: Neuroradiology Service, Cardarelli Hospital, Catullo 30, 80122 Naples, Italy. Tel.: +39 0815752281; fax: +39 0815752281. E-mail addresses: [email protected] (S. Mangiafico), [email protected] (G. Guarnieri), [email protected] (A. Consoli), [email protected] (G. Ambrosanio), [email protected] (M. Muto). 0720-048X/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejrad.2012.11.005
of “incidental finding” of asymptomatic UIAs are frequent and increasing, making hard, complex and controversial the decision about the indication to the treatment. The rationale to treat an UIA is to prevent the rupture and its consequent SAH and all complications derived from hemorrhage and to reduce or eliminate nerve palsy, if present. Although this statement is correct, the indication to treat a UIA should be based on a correct balance between the natural history of UIA and treatment risk (surgery or endovascular). The natural history of UIAs and treatment outcomes are influenced by: - Patient’s clinical history, such as previous aneurysmal SAH, age, and coexisting medical conditions (collagenopathy and other genetic condition), alcohol-abuse, smoking; - Aneurysm characteristics, such as size, location, and morphology; - Strategy management, such as the experience of the surgical or endovascular team and the treating hospital. In the last 10 years and more, two important large multicenter studies were performed in order to analysis of all these factors and to evaluate the best treatment option for UIAs [5,6]. Although the criticisms and controversies derived from these studies, they represent the basis for the management of UIAs and they can be used to search the best indication treatment. The aim of this paper is to try to synthesize the indication to endovascular treatment (EVT), when and how to treat an UIA.
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2. Indications to treatment: when to treat an UIA? When to treat an UIA? This is the real problem! Many factors can influence the choice and the type of treatment of UIAs according to ISUIA 1 and 2 studies: (1) Patient clinical history, such as age, and coexisting medical conditions, alcohol-abuse, smoking, previous aneurysmal SAH; (2) Aneurysm characteristics, such as size, location, morphology and its symptom; (3) The hemodynamic environment; (4) Factors in management, such as the experience of the surgical or endovascular team and the treating hospital. All these factors can be analyzed and combined each other to make the choice between to treat and not to treat. (1) “Patient clinical history” is one of the elements to research. Sex, age and patient-environment influence the choice. By ISUIA 1 and 2 [5,6], aneurysms were more frequent in female-group (55–60%) than male-group, and by ISAT study more SAH occurred in female-group [2]. The age is an important factor that can influence the natural history of UIAs and its outcome. Patient with an age over than 60 is associated with a statistically significant increased risk of rupture. About the outcome, as illustrated by ISUIA 2, a morbidity and mortality rate of 6.5% for patients <45 years old, 14.4% for patients 45–65 years old, and 32% for patients >64 years old were registered [6]. In any case, even if the aneurysm is discovered in early-age, the choice of treatment could be considered during the follow up time according to the 5-year cumulative rupture risk rate by ISUIA 2 in order to prevent rupture [6]. Smoking, hypertension and alcohol-abuse represent a risk factor to develop aneurysm and to increase the incidence of rupture, even if those factors are not statistically significant in other experience [7]. The presence of inherited diseases (adult polycystic kidney diseases, Ehlers–Danlos Syndrome, NF1, Bourneville disease, FM dysplasia, Marfan diseases) is associated with a higher risk of developing an aneurysm: 7–40% of ADPCKD-patients have a UA [5]. The familial history of SAH represents a risk factor and it means that there may be a genetic involvement. These familial predispositions are recognized as a non-modifiable risk factor for the formation and rupture of intracranial aneurysms. The Familial Intracranial Aneurysm (FIA), a multicenter international study, assess the genetic and other risk factors for formation and rupture of UIA comparing the FIA study cohort with the ISUIA-data with regard to patient demographic data, aneurysm location and multiplicity. To improve comparability, all patients in the ISUIA who had a family history of IAs or subarachnoid hemorrhage were excluded by the study, as well as all patients in both cohorts who had a ruptured IA prior to study entry: of 983 patients enrolled in the FIA study with definite or probable IAs, 511 met the inclusion criteria for this analysis. Of the 4059 patients in the ISUIA study, 983 had a previous IA rupture and 657 of the remainder had a positive family history, leaving 2419 individuals in the analysis. Multiple aneurysms were more common in the FIA patients (35.6% vs. 27.9%, p < 0.001). The FIA patients had a higher proportion of IAs located in the middle cerebral artery (28.6% vs. 24.9%), whereas ISUIA patients had a higher proportion of posterior communicating artery IAs (13.7% vs. 8.2%, p = 0.016). Heritable structural vulnerability may account for differences in IA multiplicity and location. Several investigations into the underlying genetic mechanisms of IA formation are ongoing [8]. (2) “Aneurysm characteristics”: size, type, location, morphology and “symptoms” influence the indication to the treatment.
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The aneurysm sizes, associated to the location (anterior or posterior circulation), represent the best predictor of rupture and the best indication criteria. By ISUIA 1 data [5], the rate of rupture of aneurysms of patients without prior SAH affected by UIA <10 mm was less than 0.05%/year, while in the prior SAH patients-group, the rate was approximately 11 times as high (0.5%/year). The rupture rate of aneurysms that were 10 mm or more in diameter was less than 1%/year in both groups, but in group 1, the rate was 6% the first year for giant aneurysms (25 mm in diameter). Rupture occurs more frequent for aneurysms located at posterior circulation (posterior communicating artery, vertebro-basilar/posterior cerebral, and basilar tip). Among the patients without prior SAH with posterior communicating, vertebro-basilar/posterior cerebral, and basilar tip UIAs >25 mm in diameter, the risk of rupture was 45% at 7.5 years; 10–24-mm UIAs and, 10-mm UIAs in the same locations carried rupture risks of 15% and 2% over 7.5 years, respectively. In all other locations, the rupture risks at 7.5 years for >25-mm, 10–24-mm, and 10-mm UIAs were 8%, 3%, and 0%, respectively [5–7,9]. In the USUIA 2 the 5-year cumulative rupture rates for patients who did not have a history of subarachnoid hemorrhage with aneurysms located in internal carotid artery, anterior communicating or anterior cerebral artery, or middle cerebral artery were 0%, 2.6%, 14.5%, and 40% for aneurysms less than 7 mm, 7–12 mm, 13–24 mm, and 25 mm or greater, respectively, compared with rates of 2.5%, 14.5%, 18.4%, and 50%, respectively, for the same size categories involving posterior circulation and posterior communicating artery aneurysms [6]. For the very small aneurysms (≤3 mm) the management and treatment indication remain unclear. For this size, the risk of rupture in the natural history is very low (according to ISUIA 2 the rupture rate for this size is approximately 0%/year) compared to the endovascular complications rate (thromboembolic events and intraoperative rupture). In the ATENA subgroup study, Pierot et al. reported a similar endovascular risk treatment in patients with very small or with large aneurysm. Because the risk of spontaneous rupture is lower in very small aneurysm their management will include follow up MRI and active treatment in case of morphological modification [10]. Considering the statement that cerebral aneurism formation is based on wall-vessel alteration (aneurismal wall has a lower level of elastin and collagen; ruptured aneurysm has an increased expression of elastase compared to unruptured aneurysm; extracellular matrix alteration with less and brief fibers combined to environment risk factors), the presence of symptoms such as mass effect, nerve palsy (according to its location) in a patient with a known or unknown UIAs, an abnormal headache resistant to medical therapy supposes an aneurysm grown-activity prior its rupture [11]. In this case symptoms onset justifies the indication treatment as soon as possible. (3) The hemodynamic environment in unruptured aneurysm could influence the natural history. Hemodynamic factors are thought to play an important role in the initiation, growth, and rupture of cerebral aneurysms. They act on the vessel wall and they can be distinguished in: • Hydrostatic pressure: arterial blood pressure. • Dynamic pressure: circulating blood impinges on the vessel wall. • Shear stress: frictional shear force on the endothelium parallel to the vessel wall. The Maximum Shear Stress (MSS) represents the interaction between different layers of blood within the aneurysm and it has an important role in platelets activation with thrombus formation; the Wall Shear Stress (WSS) represents the moving blood strength
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on the endothelial surface. This stress acts on the function and on the gene expression of endothelial cells playing an important role on the shape and structure of endothelial cells themselves. Rupture occurs when wall stress exceeds wall strength. Enlargement of aneurysms appears to be governed by the interaction between hemodynamic loads and mechanic–biologic responses of the cellular elements of the wall, resulting in a weakening of the wall. High WSS level seems to contribute to the initiation and to development of aneurysm. At contrary, low WSS level seems to be related to the growth and rupture of aneurysms causing a remodeling of arterial wall. Indeed, low WSS level generates the proliferation and endothelial apoptosis, change of cellular secretion with abnormal vasoconstrictor factor, inflammatory factor and pro-thrombotic mediators: in the meanwhile there is also a reduction of vasodilator and anti-oxidant factors [12]. Concentrated inflow streams and WSS distributions with elevated levels of MWSS and low aneurysmal viscous dissipation are statistically associated with a clinical history of prior aneurysm rupture. In contrast, the area and total viscous shear force applied in the aneurysm region subjected to abnormally low WSS levels are not [13]. (4) Factors in management, such as the experience of the surgical or endovascular team and the treating hospital. The overall rate of surgery-related morbidity and mortality is estimated to 17.5% in patients-group without prior SAH and 13.6% in patients-group with prior SAH at 30 days and it was 15.7% and 13% respectively, at 1 year [6,7]. Age independently predicted surgical outcome. The ISUIAs group concluded that the likelihood of rupture of UIAs that were less than 10 mm in diameter was exceedingly low among patients in group 1 and was substantially higher among those in group 2. The risk of morbidity and mortality related to surgery greatly exceeded the 7.5-year risk of rupture among patients in group 1 with unruptured intracranial aneurysms smaller than 10 mm [5,6]. By the ATENA study data, the EVT of UIAs is feasible in a high percentage of cases with low morbidity and mortality rates compared to their natural history. The authors prospectively and consecutively analyzed 649 patients harboring a total of 1100 aneurysms from 27 Canadian and French neuro-interventional centers treated by endovascular coil embolization. They registered technical adverse events with or without clinical modification in 15.4% of patients and included thromboembolic complications (7.1% per procedure), intraoperative rupture (2.6% per procedure), and device-related problems (2.9% per procedure). Adverse events associated with transient or permanent neurological deficit or death were encountered in 5.4% of cases. The 1-month morbidity and mortality rates were 1.7% and 1.4%, respectively [10]. 3. Endovascular therapy and objectives, how to treat The first historical attempts of endovascular treatment of unruptured intracranial aneurysms were performed after the introduction of detachable coils in 1991. A microcatheter was positioned within the aneurysmal sac and coils were released to provide a dense packing of coils to exclude the aneurysm from the intracranial circulation (Fig. 1). Since late ‘90s the introduction of remodeling balloons and intracranial stents encouraged the development of the treatment of broad-based aneurysms that could not be treated with the simple coiling technique. During the late months of 2008 Flow Diverter stents (FDs) were proposed for the treatment of intracranial aneurysms with a different rationale: the blood flow is deviated through the parent vessel and is slowed and reduced within the
aneurysm, encouraging the progressive thrombosis of the sac. The last generation of devices for the treatment of saccular intracranial aneurysms focuses on the intrasaccular flow-diversion, aiming at the exclusion of the sac by positioning the device within the aneurismal sac without the release of stents within the parent vessel. Several studies, registries and series have been published to describe the advantages and the risks of these techniques and devices, reporting reasonable and encouraging results about the treatment of unruptured saccular intracranial aneurysms, although a commonly accepted strategy has not been established. The morphologic features of the aneurysm, the clinical picture of the patient, the operators’ experience and the availability of the devices seem to be the most influencing factors regarding the choice of the treatment technique [14]. 3.1. Wall-side aneurysms of the internal carotid artery The aneurysms localized on the lateral side of a parent vessel (ICA siphon), may be treated with different modalities and the size of the sac, the dome-to-neck ratio and the presence of arterial branches arising from the sac (posterior communicating artery, anterior choroidal artery, ophthalmic artery) are considered decisional factors for the choice of the treatment technique. Although an aneurysm with a small-sized neck may allow the simple coiling of the sac, wide-necked aneurysms with a dome-to-neck ratio <1.5 would require the use of devices to provide an assisted coiling and maintain the patency of the parent vessel. Series published in literature reported high rates of adequate occlusions for stent- and balloon-assisted coiling (64.2–94%) [15,16]. The efficacy of these two treatment techniques is also supported by reasonable rates of intra-procedural complications and consequent mortality and morbidity rates (respectively 0–7.4% and 0.2–4.6%) [17,18]. Contrarily to the RT, the main advantage to perform a stent-assisted coiling in a wall-side aneurysm is to avoid a flow arrest in the parent vessel. Indeed, the use of remodeling balloons may provide a higher coverage of the neck and of the branches with arising closely to the neck; this aspect may result particularly useful in the treatment of unruptured aneurysms of the posterior wall of the ICA and in presence of a fetal posterior cerebral artery. Furthermore, aneurysms localized at the lateral wall of the ICA, particularly in case of accentuated vascular tortuosity when it may be difficult to identify the neck from the profile of the ICA, the use of RT could result safer since the balloon allows to obtain the complete exclusion of the aneurysm even if a clear view of the neck is recognizable only with axial projections (“down the barrel” projection). However, the dual antiplatelet therapy protocol, the risk of perforation due to the guide wires and the recanalization rates represent critical issues for both the techniques. Nevertheless, the development of the micro technology provided new solutions to reduce the risks secondary to the technical aspects of the procedure, such as no-tip detachable stents, small-sized stents deployed through smaller microcatheters or double-lumen balloons that may be used to perform both treatments during the same procedure. Currently, there is no consensus about the length and the dose of a dual antiplatelet therapy administered for the use of intracranial stents, since the pharmacological approach derived from cardiologic protocols. The increasing use of the FDs for these aneurysms provided encouraging results for the treatment of these aneurysms even if some aspects should still be discussed. Large or giant aneurysms, diffuse dysplasia of the ICA with the presence of multiple aneurysms and aneurysms with an expected higher recanalization rate (broad-based medium-large carotid ophthalmic aneurysms) may be considered a good target for FDs (Fig. 2). Anyway, post-procedural ruptures have been described [18–20] and raised some questions about the necessity of a partial coiling in association with the use of a FD. Finally, in those cases in which
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Fig. 1. Pre-treatment evaluation of a 11 × 8 × 5 mm unruptured, symptomatic aneurysm of the sovra-ophtalmic ICA segment in working projections (a). Final angiogram at the end of the procedure performed by “coiling only technique” using Penumbra Coils System® only (b–d). At 1 year follow-up, the T1W-post c.e. MRI and VR-DCEMRA reconstruction show the occlusion of the aneurysm (e–g).
Fig. 2. Pre-treatment evaluation of a 15 × 10 mm unruptured aneurysm of the ICA in working projections (a and b). Manual carotid occlusion test during injection in the contralateral ICA showing the presence of good flow compensation through the ACoA (c). Deployment of the Flow Diverter stent (d). Pipeline Embolization Device 4.5 × 16 mm, ev3-Covidien, Irvine, California. Six months angiographic follow-up (f).
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neither the conventional techniques nor the FDs could be used (marked vascular tortuosity), in giant intracavernous aneurysm or partially thrombosed ones determining relevant mass effect also the Parent Vessel Occlusion should be considered after a Balloon Occlusion Test is performed.
3.2. Bifurcational aneurysms (middle cerebral artery, bifurcation of the ICA, basilar apex) The endovascular treatment of an aneurysm localized at a bifurcation represents a challenging aspect because of the necessity to maintain the patency of the branches. An accurate pre-operative angiographic assessment is mandatory for the choice of the treatment technique since the morphological characteristics, the precise position of the aneurysm, if decentred on one of the branches, the presence and the number of arteries originating from the sac (MCA trifurcations), the angle of origin (higher difficulty if branches have recurrent origin) and the orientation of the sac itself are the most important factors involved in the planning of the endovascular strategy. In case of a broad-based aneurysm the goal of the treatment is to reconstruct the correct shape of the bifurcation and, consequently, the neck of the aneurysm. The position of the “aneurismal complex” (sac + neck) with respect to the bifurcation may indicate the necessity to protect one or more branches and to use one or more devices to reach this result, so that if an aneurysm is decentred on one of the branches the use of only one stent or balloon could be sufficient. In those cases in which the aneurysmal sac is symmetrically localized at a bifurcation, more than one arterial branch may origin from the sac and either the “Y-stenting” (Fig. 3) or the “kissing balloon” remodeling technique (Fig. 4), or in simple cases a single compliant balloon adapting to the shape of the bifurcation, may be considered. A few data are reported in literature about these two techniques, that, although more laborious procedures seem to provide encouraging results in terms of safety and effectiveness. The role of FDs is very controversial in the treatment of bifurcational aneurysms: the flow diversion toward one of the two sides could determine a severe hypoperfusion within the other branch with consequent possible ischemic complications, although collaterals may supply these events. In the last couple of years, the experience with intra-saccular flow diverters (LUNA, WEB) is providing interesting results in this type of aneurysms, although some concerns still remain, such as the compliance of the device to the shape of the aneurysm that could determine incomplete occlusions difficult to be retreated.
3.3. “H-shape” aneurysms (anterior communicating artery) Those ones localized at the ACoA represent a particular subgroup of bifurcational aneurysm. These aneurysms may be positioned centrally on the ACoA or be decentred on one of the two A1–A2 corners and that determine the necessity to protect one or both anterior cerebral arteries during the coiling. Another critical point is the presence of symmetrical A1 segments: the hypoplasia of one of these two segments underlines the necessity of a monolateral approach. RT with a balloon through the ACoA, X-stenting (Fig. 5) and Y-stenting in case of hypoplasia of one of the two A1 segments and parallel stenting (two stents positioned from A1 to A2 in both sides) may be useful techniques and should be used depending on the operators’ experience. However, the use of balloon in small arteries, such as the ACoA, may expose to higher risk of over-inflation and consequent rupture of the aneurismal neck and prolonged occlusions may determine ischemic complications secondary to the hypoperfusion of perforating arteries (recurrent artery of heubner).
4. Pharmacological aspects in intracranial stenting According to cardiological protocols, a dual antiplatelet therapy is usually administered when a stent is placed intracranially. Patients treated with stent-assisted coiling or FDs receive a pretreatment (at least 7–10 days before in our clinical experience) with Clopidogrel 75 mg/day or Ticlopidine 250 mg (2 tablets/day), ASA 300 mg/day and gastric protector 1 tablet/day (Lansoprazole in most cases) considering all known cross-reactions [21]. Platelet inhibition may be evaluated with in vitro tests that calculate the residual platelet activity and the specific individual response to Thyenopiridines (Clopidogrel or Ticlopidine, correct values for a good platelet inhibition should be <70%) or to ASA (good results if residual platelet function is <20%) one or 2 days before the procedure. This algorithm may reduce the risk to release a stent in potential non-responder patients. Furthermore, another critical issue is the length of the dual antiplatelet therapy. Our experience suggested us to maintain a dual antiplatelet therapy for 6 months when a FD stent or at least two overlapping stents (Y- or X-stenting, telescopic stenting) are released to prevent the risk of ischemic complications secondary to the early suspension of one of the antiplatelet drugs (usually Thyenopiridines), probably due to longer times of re-endothelization of the stents. A 3 months therapy may be considered sufficient in those procedures in which a single stent is used. However, no certain data are present and further studies should be carried out to assess the most adequate dose and length of the pharmacological therapy.
5. Recanalization aneurysm rate for the EVT Aneurysm rest and recurrence are two important technical limits of EVT. The magnitude and clinical significance of these drawbacks are now well-known and embolized-patients need to have a longer follow-up compared to clipped patients [22]. Patients with ruptured aneurysm have a higher incidence of recurrence rate compared to patients affected by unruptured aneurysm. Nguyen et al. found a recanalization rate of 53.5% in the ruptured aneurysms versus 22.5% for unruptured aneurysms (p = 0.001) requiring a re-treatment by either re-coiling (with or without stent/balloon assistance) or surgical clipping [23]. This different finding between ruptured and unruptured aneurysm patients is due to a different morphology of the aneurysm wall. The wall of ruptured aneurysms is fragile compared to that of unruptured aneurysms. Histological analysis has shown that unruptured aneurysms are more likely to have thick intimalike walls than ruptured aneurysms which are more likely to have thin degenerate walls with hyaline deposits. Frosen et al. [24,25] postulate that the inflammatory response with infiltration of macrophages and T-cells as well as smooth muscle cell proliferation may have been present prior to rupture leading to wall instability. Multiple factors can influence the recanalization rate such as the used technique (coiling alone, balloon remodeling, coiling + stenting), the coiling-packing, the size and the site of aneurysm, and the type of devices used (opened or closed stents + coiling, flow diversion stent). Coiling technique has a higher incidence of recurrence rate, estimated up to 33.6% of cases, but there is no significant difference between aneurysms treated with complex coils only and those treated with helical ones [22,26]. Incomplete aneurysm occlusion with residual neck or aneurysm, has been identified as a significant predictor of recurrence. Moret et al. found that an initial incomplete occlusion conferred a higher risk of recurrence, especially in the group of
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Fig. 3. Pre-treatment angiographic assessment of a 9 × 7 mm unruptured MCA aneurysm in working projections (a and b). Microcatheterization of the superior branch of the MCA and initial deployment of the stent (Enterprise stent 4.5 × 37, Codman Neurovascular, J&J, Raynham, Massachusetts). Another microcatheter is already within the sac (c, jailing technique). Navigation within the other bifurcational branch through the first stent and subsequent deployment of the second one (Enterprise stent 4.5 × 28, Codman Neurovascular, J&J, Raynham, Massachusetts) (d). Coiling of the sac with Y-stenting (e). Final angiographic evaluation showing the complete occlusion of the sac (f).
aneurysms with larger dimensions. One interpretation is that complete obliteration of the lesion is important to decrease the number of early recurrences, and this can be achieved more frequently with technical advances, such as the use of complex coils or the balloon remodeling technique or stenting + coiling [26]. Technical advances, such as closed cell stenting + coiling, for unruptured cerebral aneurysms assure a lower incidence of recurrence, reduced to 10%, with a re-treatment rate to 5.8% [27].
The durability of endovascular coil occlusion of intracranial aneurysms is thought to depend on density of packing achieved within the aneurysm sac, commonly known as volumetric percentage occlusion (VPO) [28]. According to the “coiling-packing grade”, Moret et al. [26] did not find a significantly different numbers of recurring lesions between patients with a packing <24% and ≥24%, treated with “standard” bare-platinum coils.
Fig. 4. Pre-treatment DSA (Digital Subtraction Angiography) evaluation of a 6 × 5 mm aneurysm of the MCA bifurcation in working projections (a–b). Positioning of two remodeling balloons (2 Hyperglide 4 × 15, ev3-Covidien, Irvine, California) within both bifurcational branches (c). Kissing balloon assisted-coiling (d). Final 3D-DSA evaluation with subtracted images (e). Final angiogram at the end of the procedure (f).
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Fig. 5. Pre-treatment angiographic evaluation of an unruptured 5 mm aneurysm of the ACoA in frontal view (a). Positioning of two microcatheters (Prowler Select Plus 90◦ , Codman Neurovascular, Raynham, Massachusetts) for stent delivery (Enterprise stent 4.5 × 28 and 4.5 × 22, Codman Neurovascular, J&J, Raynham, Massachusetts) crossing through the ACoA, directed from A1 to the contralateral A2 segment of the ACA: the “X-shape” (b). Coiling of the sac after the deployment of the two stents (c). Final angiograms at the end of the procedure in frontal (d) and lateral (e) view showing the complete occlusion of the sac. 3D-DSA evaluation without subtracted images showing the reconstruction of the anatomy of the ACoA.
The hydrogel-coated coils (HydroCoils) embolization, a platinum coils covered with a hydrophilic polymer that swells in blood, seems to achieve a greater aneurysm packing density with decreased coil length with lower recurrence and retreatment rates. In fact, Gaba et al. [29] found a lower aneurysm recurrence rates (17%) at 1 year follow-up in fifty aneurysms embolized primarily using HydroCoils compared with 57 volumeand shape-matched aneurysms treated with standard platinum coils. Mascitelli et al. [30] achieved a statistically significant greater packing density (36.8%) with fewer coils compared with “conventional” coils using the Penumbra Coil 400 System, a new generation of softer platinum coils with a larger diameter than conventional embolic coils, registering, at 1 year follow-up, a lower recurrence rate. The larger diameter with the inherent softness of the coils should result in a higher packing density of coils within aneurysms that is marketed as having up to 400% more volume per unit length than conventional embolic coils. Large aneurysms (>10 mm) treated with coils have a greater propensity to recur than do smaller aneurysms [22]. According to the site of aneurysms, basilar bifurcation, ophthalmic carotid artery, anterior communicating artery, posterior communicating artery and MCA bifurcation, the recurrence rate is respectively up to 39.4%, 26.0%, 25.0%, 37.2% and 32.1% [22,31]. The incidence of recurrence could be reduced by the introduction of new generation stent: The Flow Diverter stent (FD). They have the property of forming high-coverage mesh on the neck of the aneurysm to reduce the blood flow into the sac, and subsequently to induce the aneurysm thrombosis, all while preserving the patency of adjacent small vessels. In fact, Berge et al. [32] found a complete aneurysm occlusion, without any recurrence, in 84% of cases. While Pistocchi et al. [33] found that fifteen of 19 aneurysms (78.9%) treated with FDs against 4 of 4 of aneurysms (100%) treated with FDs and coils were occluded with no angiographic recurrence of initially totally occluded aneurysms.
6. Conclusions The life cycle of aneurysms is a complex process with multiple actors where the flow dynamics play a key role in the process. The treatment of UIAs remains complex and not clearly defined. The endovascular treatment may be considered a safe and effective approach of unruptured intracranial aneurysms, considering the technical developments that allow the complete occlusion of the aneurismal sac also in challenging situations, such as the bifurcational aneurysms. These encouraging results, comparable to surgical series, remark the advantage of a minimally invasive treatment, although some issues, such as the correct selection of the patients in terms of indication to treat, the length of the followup and the pharmacological protocols still remain debated and in some cases controversies. Conflict of interest None. References [1] Raymond J, Kotowski M, Darsaut TE, Molyneux AJ, Kerr RS. Ruptured aneurysms and the International Subarachnoid Aneurysm Trial (ISAT): what is known and what remains to be questioned. Neuro-Chirurgie 2012;58(2–3):103–14. [2] Molyneux AJ, Kerr RS, Yu LM, et al. International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet 2005;366(9488):809–17. [3] Ohkuma H, Fujita S, Suzuki S. Incidence of aneurysmal subarachnoid hemorrhage in Shimokita, Japan, from 1989 to 1998. Stroke 2002;33:195–9. [4] Hijdra A, Braakman R, van Gijn J, Vermeulen M, van Crevel H. Aneurysmal subarachnoid hemorrhage. Complications and outcome in a hospital population. Stroke 1987;18(6):1061–7. [5] ISUIA Investigators. Unruptured intracranial aneurysms: risks of rupture and risks of surgical intervention. The New England Journal of Medicine 1998;339:1725–33.
S. Mangiafico et al. / European Journal of Radiology 82 (2013) 1638–1645 [6] Wiebers DO, Whisnant JP, Huston 3rd J, et al. International study of unruptured intracranial aneurysms investigators unruptured intracranial aneurysms natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 2003;362:103–10. [7] Wermer MJ, van der Schaaf IC, Algra A, Rinkel GJ. Risk of rupture of unruptured intracranial aneurysms in relation to patient and aneurysm characteristics: an updated meta-analysis. Stroke 2007;38(4):1404–10. [8] Mackey J, Brown Jr RD, Moomaw CJ, et al. FIA and ISUIA investigators. Unruptured intracranial aneurysms in the familial intracranial aneurysm and international study of unruptured intracranial aneurysms cohorts: differences in multiplicity and location. Journal of Neurosurgery 2012;117(1):60–4. [9] Bederson JB, Awad IA, Wiebers DO, et al. Recommendations for the management of patients with unruptured intracranial aneurysms: a Statement for healthcare professionals from the Stroke Council of the American Heart Association. Stroke 2000;31(11):2742–50. [10] Pierot L, Barbe C, Spelle L. ATENA investigators endovascular treatment of very small unruptured aneurysms: rate of procedural complications, clinical outcome, and anatomical results. Stroke 2010;41(12):2855–9. [11] Ruigrok YM, Rinkel GJ. Genetics of intracranial aneurysms. Stroke 2008;39:1049–55. [12] Boussel L, Rayz V, Martin A, et al. Phase-contrast magnetic resonance imaging measurements in intracranial aneurysms in vivo of flow patterns, velocity fields, and wall shear stress: comparison with computational fluid dynamics. Magnetic Resonance in Medicine 2009;61(2):409–17. [13] Cebral JR, Mut F, Weir J, Putman CM. Association of hemodynamic characteristics and cerebral aneurysm rupture. AJNR American Journal of Neuroradiology 2011;32:264–70. [14] Briganti F, Napoli M, Tortora F, et al. Italian multicenter experience with flow-diverter devices for intracranial unruptured aneurysm treatment with periprocedural complications-a retrospective data analysis. Neuroradiology 2012;54(10):1145–52. [15] Moret J, Cognard C, Weill A, Castaings L, Rey A. The “Remodelling technique” in the treatment of wide neck intracranial aneurysms. Angiographic results and clinical follow-up in 56 cases. Interventional Neuroradiology 1997;30(3(1)):21–35. [16] Biondi A, Janardhan V, Katz JM, Salvaggio K, Riina HA, Gobin YP. Neuroform stent-assisted coil embolization of wide-neck intracranial aneurysms: strategies in stent deployment and midterm follow-up. Neurosurgery 2007;61(3):460–8. [17] Fiorella D, Albuquerque FT, Woo H, Rasmussen PA, Masaryk TJ, McDougall CG. Neuroform stent-assisted aneurysm treatment: evolving treatment strategies, complications and results of long term follow-up. Journal of Neurointerventional Surgery 2010;2:16–22. [18] Mocco J, Snyder KV, Albuquerque FC, et al. Treatment of intracranial aneurysms with the enterprise stent: a multicenter registry. Journal of Neurosurgery 2009;110:35–9. [19] Yu SC, Kwok CK, Cheng PW, et al. Intracranial aneurysms: midterm outcome of pipeline embolization device – a prospective study in 143 patients with 178 aneurysms. Radiology 2012 [Epub ahead of print, September 20].
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[20] Nelson PK, Lylyk P, Szikora I, Wetzel SG, Wanke I, Fiorella D. The pipeline embolization device for the intracranial treatment of aneurysms trial. American Journal of Neuroradiology 2011;32(1):34–40. ˜ C, Jover E, Hernández-Romero D, et al. Interactions between [21] Munoz-Esparza clopidogrel and proton pump inhibitors: a review of evidence. Current Medicinal Chemistry 2011;18(16):2386–400. [22] Raymond J, Guilbert F, Weill A, et al. Longterm angiographic recurrences after selective endovascular treatment of aneurysms with detachable coils. Stroke 2003;34:1398–403. [23] Nguyen TN, Hoh BL, Amin-Hanjani S, et al. Comparison of ruptured vs. unruptured aneurysms in recanalization after coil embolization. Surgical Neurology 2007;68:19–23. I.Y.L. [24] Frosen J, Piippo A, Paetau A, et al. Remodeling of saccular cerebral artery aneurysm wall is associated with rupture: histological analysis of 24 unruptured and 42 ruptured cases. Stroke 2004;35:2287–93. [25] Kataoka K, Taneda M, Asai T, et al. Structural fragility and inflammatory response of ruptured cerebral aneurysms: a comparative study between ruptured and unruptured cerebral aneurysms. Stroke 1999;30: 1396–401. [26] Piotin M, Spelle L, Mounayer C, et al. Intracranial aneurysms: treatment with bare platinum coils – aneurysm packing, complex coils, and angiographic recurrence. Radiology 2007;243(2):500–8. [27] Wakhloo I, Linfante CF, Silva EA, et al. Closed-cell stent for coil embolization of intracranial aneurysms: clinical and angiographic results. AJNR American Journal of Neuroradiology 2012;33:1651–6. [28] Tamatani S, Ito Y, Abe H, Koike T, Takeuchi S, Tanaka R. Evaluation of the stability of aneurysms after embolization with detachable coils: correlation between stability of aneurysms and embolized volume of aneurysms. AJNR American Journal of Neuroradiology 2002;23: 762–7. [29] Gaba RC, Ansari SA, Roy SS, Malisch TW. Embolization of intracranial aneurysms with hydrogel-coated coils versus inert platinum coils: effects on packing density, coil length and quantity, procedure performance, cost, length of hospital stay, and durability of therapy. Stroke 2006;37(6): 1443–50. [30] Mascitelli JR, Patel AA, Kamath AA, Moyle H, Patel AB. Initial experience with Penumbra Coil 400 versus standard coils in embolization of cerebral aneurysms: a retrospective review. Journal of Neurointerventional Surgery 2012 [Epub ahead of print, September 19]. [31] Corns R, Zebian B, Tait MJ, et al. Prevalence of recurrence and retreatment of ruptured intracranial aneurysms treated with endovascular coil occlusion. British Journal of Neurosurgery 2012 [Epub ahead of print, July 5]. [32] Berge J, Biondi A, Machi P, Pierot L, Barreau X, Bonafé A. Flow-diverter silk stent for the treatment of intracranial aneurysms: 1-year follow-up in a multicenter study. AJNR American Journal of Neuroradiology 2012;33(6): 1150–5. [33] Pistocchi S, Blanc R, Bartolini B, Piotin M. Flow diverters at and beyond the level of the circle of willis for the treatment of intracranial aneurysms. Stroke 2012;43(4):1032–8.
Contents lists available at ScienceDirect
European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Endovascular strategy for unruptured cerebral aneurysms S. Mangiafico a , G. Guarnieri b,∗ , A. Consoli a , G. Ambrosanio b , M. Muto b a b
Interventional Neuroradiology Unit, Careggi University Hospital, Florence, Italy Neuroradiology Service, Cardarelli Hospital, Naples, Italy
a r t i c l e
i n f o
Article history: Received 1 November 2012 Accepted 2 November 2012 Keywords: Unruptured intracranial aneurysms Wall-side aneurysms Bifurcational aneurysms “H-shape” aneurysms Flow-diverter stenting Y-stenting Recanalization cerebral aneurysm Cerebral aneursysm Endovascular treatment Angiography
a b s t r a c t The treatment of unruptured intracranial aneurysms (UIAs) remains complex and not clearly defined. While for ruptured intracranial aneurysms the management and the treatment option (surgery or endovascular treatment) are well defined by several trials, for asymptomatic UIAs the best management is still currently uncertain. The rationale to treat an UIA is to prevent the rupture and its consequent SAH and all complications derived from hemorrhage or reduce/eliminate neurological palsy. Although this statement is correct, the indication to treat an UIA should be based on a correct balance between the natural history of UIA and treatment risk. Patient’s clinical history, aneurysm characteristics, and strategy management influence the natural history of UIAs and treatment outcomes. In the last 10 years and more, two important large multicenter studies were performed in order to analysis of all these factors and to evaluate the best treatment option for UIAs. The aim of this paper is to try to synthesize the possible indications to the endovascular treatment (EVT), when and how to treat an UIA. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The treatment of unruptured intracranial aneurysms (UIAs) remains complex and not clearly defined. While for ruptured intracranial aneurysms the management and the treatment option (surgery or endovascular treatment) are well defined by several trials [1,2]; for asymptomatic UIAs the best management is still currently uncertain. The prevalence of UIAs is estimated at 2–4% of the adult population with an incidence of subarachnoid hemorrhage (SAH) due to their rupture at 10/100,000/year [3]. High morbidity and mortality (45–75%) rate due to SAH are very well known and described, despite the current technique of treatment and reanimation assistance [4]. Despite the fact generally intracranial aneurisms are asymptomatics up to their rupture, they can have an unspecific symptom as frequent headache resistant to medical treatment or they can be disclosed by nerve palsy or compression effect to nervous structures. Thanks to the great development of mini-invasive imaging techniques in the last 20 years with CTA or MRA, the incidence
∗ Corresponding author at: Neuroradiology Service, Cardarelli Hospital, Catullo 30, 80122 Naples, Italy. Tel.: +39 0815752281; fax: +39 0815752281. E-mail addresses: [email protected] (S. Mangiafico), [email protected] (G. Guarnieri), [email protected] (A. Consoli), [email protected] (G. Ambrosanio), [email protected] (M. Muto). 0720-048X/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejrad.2012.11.005
of “incidental finding” of asymptomatic UIAs are frequent and increasing, making hard, complex and controversial the decision about the indication to the treatment. The rationale to treat an UIA is to prevent the rupture and its consequent SAH and all complications derived from hemorrhage and to reduce or eliminate nerve palsy, if present. Although this statement is correct, the indication to treat a UIA should be based on a correct balance between the natural history of UIA and treatment risk (surgery or endovascular). The natural history of UIAs and treatment outcomes are influenced by: - Patient’s clinical history, such as previous aneurysmal SAH, age, and coexisting medical conditions (collagenopathy and other genetic condition), alcohol-abuse, smoking; - Aneurysm characteristics, such as size, location, and morphology; - Strategy management, such as the experience of the surgical or endovascular team and the treating hospital. In the last 10 years and more, two important large multicenter studies were performed in order to analysis of all these factors and to evaluate the best treatment option for UIAs [5,6]. Although the criticisms and controversies derived from these studies, they represent the basis for the management of UIAs and they can be used to search the best indication treatment. The aim of this paper is to try to synthesize the indication to endovascular treatment (EVT), when and how to treat an UIA.
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2. Indications to treatment: when to treat an UIA? When to treat an UIA? This is the real problem! Many factors can influence the choice and the type of treatment of UIAs according to ISUIA 1 and 2 studies: (1) Patient clinical history, such as age, and coexisting medical conditions, alcohol-abuse, smoking, previous aneurysmal SAH; (2) Aneurysm characteristics, such as size, location, morphology and its symptom; (3) The hemodynamic environment; (4) Factors in management, such as the experience of the surgical or endovascular team and the treating hospital. All these factors can be analyzed and combined each other to make the choice between to treat and not to treat. (1) “Patient clinical history” is one of the elements to research. Sex, age and patient-environment influence the choice. By ISUIA 1 and 2 [5,6], aneurysms were more frequent in female-group (55–60%) than male-group, and by ISAT study more SAH occurred in female-group [2]. The age is an important factor that can influence the natural history of UIAs and its outcome. Patient with an age over than 60 is associated with a statistically significant increased risk of rupture. About the outcome, as illustrated by ISUIA 2, a morbidity and mortality rate of 6.5% for patients <45 years old, 14.4% for patients 45–65 years old, and 32% for patients >64 years old were registered [6]. In any case, even if the aneurysm is discovered in early-age, the choice of treatment could be considered during the follow up time according to the 5-year cumulative rupture risk rate by ISUIA 2 in order to prevent rupture [6]. Smoking, hypertension and alcohol-abuse represent a risk factor to develop aneurysm and to increase the incidence of rupture, even if those factors are not statistically significant in other experience [7]. The presence of inherited diseases (adult polycystic kidney diseases, Ehlers–Danlos Syndrome, NF1, Bourneville disease, FM dysplasia, Marfan diseases) is associated with a higher risk of developing an aneurysm: 7–40% of ADPCKD-patients have a UA [5]. The familial history of SAH represents a risk factor and it means that there may be a genetic involvement. These familial predispositions are recognized as a non-modifiable risk factor for the formation and rupture of intracranial aneurysms. The Familial Intracranial Aneurysm (FIA), a multicenter international study, assess the genetic and other risk factors for formation and rupture of UIA comparing the FIA study cohort with the ISUIA-data with regard to patient demographic data, aneurysm location and multiplicity. To improve comparability, all patients in the ISUIA who had a family history of IAs or subarachnoid hemorrhage were excluded by the study, as well as all patients in both cohorts who had a ruptured IA prior to study entry: of 983 patients enrolled in the FIA study with definite or probable IAs, 511 met the inclusion criteria for this analysis. Of the 4059 patients in the ISUIA study, 983 had a previous IA rupture and 657 of the remainder had a positive family history, leaving 2419 individuals in the analysis. Multiple aneurysms were more common in the FIA patients (35.6% vs. 27.9%, p < 0.001). The FIA patients had a higher proportion of IAs located in the middle cerebral artery (28.6% vs. 24.9%), whereas ISUIA patients had a higher proportion of posterior communicating artery IAs (13.7% vs. 8.2%, p = 0.016). Heritable structural vulnerability may account for differences in IA multiplicity and location. Several investigations into the underlying genetic mechanisms of IA formation are ongoing [8]. (2) “Aneurysm characteristics”: size, type, location, morphology and “symptoms” influence the indication to the treatment.
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The aneurysm sizes, associated to the location (anterior or posterior circulation), represent the best predictor of rupture and the best indication criteria. By ISUIA 1 data [5], the rate of rupture of aneurysms of patients without prior SAH affected by UIA <10 mm was less than 0.05%/year, while in the prior SAH patients-group, the rate was approximately 11 times as high (0.5%/year). The rupture rate of aneurysms that were 10 mm or more in diameter was less than 1%/year in both groups, but in group 1, the rate was 6% the first year for giant aneurysms (25 mm in diameter). Rupture occurs more frequent for aneurysms located at posterior circulation (posterior communicating artery, vertebro-basilar/posterior cerebral, and basilar tip). Among the patients without prior SAH with posterior communicating, vertebro-basilar/posterior cerebral, and basilar tip UIAs >25 mm in diameter, the risk of rupture was 45% at 7.5 years; 10–24-mm UIAs and, 10-mm UIAs in the same locations carried rupture risks of 15% and 2% over 7.5 years, respectively. In all other locations, the rupture risks at 7.5 years for >25-mm, 10–24-mm, and 10-mm UIAs were 8%, 3%, and 0%, respectively [5–7,9]. In the USUIA 2 the 5-year cumulative rupture rates for patients who did not have a history of subarachnoid hemorrhage with aneurysms located in internal carotid artery, anterior communicating or anterior cerebral artery, or middle cerebral artery were 0%, 2.6%, 14.5%, and 40% for aneurysms less than 7 mm, 7–12 mm, 13–24 mm, and 25 mm or greater, respectively, compared with rates of 2.5%, 14.5%, 18.4%, and 50%, respectively, for the same size categories involving posterior circulation and posterior communicating artery aneurysms [6]. For the very small aneurysms (≤3 mm) the management and treatment indication remain unclear. For this size, the risk of rupture in the natural history is very low (according to ISUIA 2 the rupture rate for this size is approximately 0%/year) compared to the endovascular complications rate (thromboembolic events and intraoperative rupture). In the ATENA subgroup study, Pierot et al. reported a similar endovascular risk treatment in patients with very small or with large aneurysm. Because the risk of spontaneous rupture is lower in very small aneurysm their management will include follow up MRI and active treatment in case of morphological modification [10]. Considering the statement that cerebral aneurism formation is based on wall-vessel alteration (aneurismal wall has a lower level of elastin and collagen; ruptured aneurysm has an increased expression of elastase compared to unruptured aneurysm; extracellular matrix alteration with less and brief fibers combined to environment risk factors), the presence of symptoms such as mass effect, nerve palsy (according to its location) in a patient with a known or unknown UIAs, an abnormal headache resistant to medical therapy supposes an aneurysm grown-activity prior its rupture [11]. In this case symptoms onset justifies the indication treatment as soon as possible. (3) The hemodynamic environment in unruptured aneurysm could influence the natural history. Hemodynamic factors are thought to play an important role in the initiation, growth, and rupture of cerebral aneurysms. They act on the vessel wall and they can be distinguished in: • Hydrostatic pressure: arterial blood pressure. • Dynamic pressure: circulating blood impinges on the vessel wall. • Shear stress: frictional shear force on the endothelium parallel to the vessel wall. The Maximum Shear Stress (MSS) represents the interaction between different layers of blood within the aneurysm and it has an important role in platelets activation with thrombus formation; the Wall Shear Stress (WSS) represents the moving blood strength
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on the endothelial surface. This stress acts on the function and on the gene expression of endothelial cells playing an important role on the shape and structure of endothelial cells themselves. Rupture occurs when wall stress exceeds wall strength. Enlargement of aneurysms appears to be governed by the interaction between hemodynamic loads and mechanic–biologic responses of the cellular elements of the wall, resulting in a weakening of the wall. High WSS level seems to contribute to the initiation and to development of aneurysm. At contrary, low WSS level seems to be related to the growth and rupture of aneurysms causing a remodeling of arterial wall. Indeed, low WSS level generates the proliferation and endothelial apoptosis, change of cellular secretion with abnormal vasoconstrictor factor, inflammatory factor and pro-thrombotic mediators: in the meanwhile there is also a reduction of vasodilator and anti-oxidant factors [12]. Concentrated inflow streams and WSS distributions with elevated levels of MWSS and low aneurysmal viscous dissipation are statistically associated with a clinical history of prior aneurysm rupture. In contrast, the area and total viscous shear force applied in the aneurysm region subjected to abnormally low WSS levels are not [13]. (4) Factors in management, such as the experience of the surgical or endovascular team and the treating hospital. The overall rate of surgery-related morbidity and mortality is estimated to 17.5% in patients-group without prior SAH and 13.6% in patients-group with prior SAH at 30 days and it was 15.7% and 13% respectively, at 1 year [6,7]. Age independently predicted surgical outcome. The ISUIAs group concluded that the likelihood of rupture of UIAs that were less than 10 mm in diameter was exceedingly low among patients in group 1 and was substantially higher among those in group 2. The risk of morbidity and mortality related to surgery greatly exceeded the 7.5-year risk of rupture among patients in group 1 with unruptured intracranial aneurysms smaller than 10 mm [5,6]. By the ATENA study data, the EVT of UIAs is feasible in a high percentage of cases with low morbidity and mortality rates compared to their natural history. The authors prospectively and consecutively analyzed 649 patients harboring a total of 1100 aneurysms from 27 Canadian and French neuro-interventional centers treated by endovascular coil embolization. They registered technical adverse events with or without clinical modification in 15.4% of patients and included thromboembolic complications (7.1% per procedure), intraoperative rupture (2.6% per procedure), and device-related problems (2.9% per procedure). Adverse events associated with transient or permanent neurological deficit or death were encountered in 5.4% of cases. The 1-month morbidity and mortality rates were 1.7% and 1.4%, respectively [10]. 3. Endovascular therapy and objectives, how to treat The first historical attempts of endovascular treatment of unruptured intracranial aneurysms were performed after the introduction of detachable coils in 1991. A microcatheter was positioned within the aneurysmal sac and coils were released to provide a dense packing of coils to exclude the aneurysm from the intracranial circulation (Fig. 1). Since late ‘90s the introduction of remodeling balloons and intracranial stents encouraged the development of the treatment of broad-based aneurysms that could not be treated with the simple coiling technique. During the late months of 2008 Flow Diverter stents (FDs) were proposed for the treatment of intracranial aneurysms with a different rationale: the blood flow is deviated through the parent vessel and is slowed and reduced within the
aneurysm, encouraging the progressive thrombosis of the sac. The last generation of devices for the treatment of saccular intracranial aneurysms focuses on the intrasaccular flow-diversion, aiming at the exclusion of the sac by positioning the device within the aneurismal sac without the release of stents within the parent vessel. Several studies, registries and series have been published to describe the advantages and the risks of these techniques and devices, reporting reasonable and encouraging results about the treatment of unruptured saccular intracranial aneurysms, although a commonly accepted strategy has not been established. The morphologic features of the aneurysm, the clinical picture of the patient, the operators’ experience and the availability of the devices seem to be the most influencing factors regarding the choice of the treatment technique [14]. 3.1. Wall-side aneurysms of the internal carotid artery The aneurysms localized on the lateral side of a parent vessel (ICA siphon), may be treated with different modalities and the size of the sac, the dome-to-neck ratio and the presence of arterial branches arising from the sac (posterior communicating artery, anterior choroidal artery, ophthalmic artery) are considered decisional factors for the choice of the treatment technique. Although an aneurysm with a small-sized neck may allow the simple coiling of the sac, wide-necked aneurysms with a dome-to-neck ratio <1.5 would require the use of devices to provide an assisted coiling and maintain the patency of the parent vessel. Series published in literature reported high rates of adequate occlusions for stent- and balloon-assisted coiling (64.2–94%) [15,16]. The efficacy of these two treatment techniques is also supported by reasonable rates of intra-procedural complications and consequent mortality and morbidity rates (respectively 0–7.4% and 0.2–4.6%) [17,18]. Contrarily to the RT, the main advantage to perform a stent-assisted coiling in a wall-side aneurysm is to avoid a flow arrest in the parent vessel. Indeed, the use of remodeling balloons may provide a higher coverage of the neck and of the branches with arising closely to the neck; this aspect may result particularly useful in the treatment of unruptured aneurysms of the posterior wall of the ICA and in presence of a fetal posterior cerebral artery. Furthermore, aneurysms localized at the lateral wall of the ICA, particularly in case of accentuated vascular tortuosity when it may be difficult to identify the neck from the profile of the ICA, the use of RT could result safer since the balloon allows to obtain the complete exclusion of the aneurysm even if a clear view of the neck is recognizable only with axial projections (“down the barrel” projection). However, the dual antiplatelet therapy protocol, the risk of perforation due to the guide wires and the recanalization rates represent critical issues for both the techniques. Nevertheless, the development of the micro technology provided new solutions to reduce the risks secondary to the technical aspects of the procedure, such as no-tip detachable stents, small-sized stents deployed through smaller microcatheters or double-lumen balloons that may be used to perform both treatments during the same procedure. Currently, there is no consensus about the length and the dose of a dual antiplatelet therapy administered for the use of intracranial stents, since the pharmacological approach derived from cardiologic protocols. The increasing use of the FDs for these aneurysms provided encouraging results for the treatment of these aneurysms even if some aspects should still be discussed. Large or giant aneurysms, diffuse dysplasia of the ICA with the presence of multiple aneurysms and aneurysms with an expected higher recanalization rate (broad-based medium-large carotid ophthalmic aneurysms) may be considered a good target for FDs (Fig. 2). Anyway, post-procedural ruptures have been described [18–20] and raised some questions about the necessity of a partial coiling in association with the use of a FD. Finally, in those cases in which
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Fig. 1. Pre-treatment evaluation of a 11 × 8 × 5 mm unruptured, symptomatic aneurysm of the sovra-ophtalmic ICA segment in working projections (a). Final angiogram at the end of the procedure performed by “coiling only technique” using Penumbra Coils System® only (b–d). At 1 year follow-up, the T1W-post c.e. MRI and VR-DCEMRA reconstruction show the occlusion of the aneurysm (e–g).
Fig. 2. Pre-treatment evaluation of a 15 × 10 mm unruptured aneurysm of the ICA in working projections (a and b). Manual carotid occlusion test during injection in the contralateral ICA showing the presence of good flow compensation through the ACoA (c). Deployment of the Flow Diverter stent (d). Pipeline Embolization Device 4.5 × 16 mm, ev3-Covidien, Irvine, California. Six months angiographic follow-up (f).
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neither the conventional techniques nor the FDs could be used (marked vascular tortuosity), in giant intracavernous aneurysm or partially thrombosed ones determining relevant mass effect also the Parent Vessel Occlusion should be considered after a Balloon Occlusion Test is performed.
3.2. Bifurcational aneurysms (middle cerebral artery, bifurcation of the ICA, basilar apex) The endovascular treatment of an aneurysm localized at a bifurcation represents a challenging aspect because of the necessity to maintain the patency of the branches. An accurate pre-operative angiographic assessment is mandatory for the choice of the treatment technique since the morphological characteristics, the precise position of the aneurysm, if decentred on one of the branches, the presence and the number of arteries originating from the sac (MCA trifurcations), the angle of origin (higher difficulty if branches have recurrent origin) and the orientation of the sac itself are the most important factors involved in the planning of the endovascular strategy. In case of a broad-based aneurysm the goal of the treatment is to reconstruct the correct shape of the bifurcation and, consequently, the neck of the aneurysm. The position of the “aneurismal complex” (sac + neck) with respect to the bifurcation may indicate the necessity to protect one or more branches and to use one or more devices to reach this result, so that if an aneurysm is decentred on one of the branches the use of only one stent or balloon could be sufficient. In those cases in which the aneurysmal sac is symmetrically localized at a bifurcation, more than one arterial branch may origin from the sac and either the “Y-stenting” (Fig. 3) or the “kissing balloon” remodeling technique (Fig. 4), or in simple cases a single compliant balloon adapting to the shape of the bifurcation, may be considered. A few data are reported in literature about these two techniques, that, although more laborious procedures seem to provide encouraging results in terms of safety and effectiveness. The role of FDs is very controversial in the treatment of bifurcational aneurysms: the flow diversion toward one of the two sides could determine a severe hypoperfusion within the other branch with consequent possible ischemic complications, although collaterals may supply these events. In the last couple of years, the experience with intra-saccular flow diverters (LUNA, WEB) is providing interesting results in this type of aneurysms, although some concerns still remain, such as the compliance of the device to the shape of the aneurysm that could determine incomplete occlusions difficult to be retreated.
3.3. “H-shape” aneurysms (anterior communicating artery) Those ones localized at the ACoA represent a particular subgroup of bifurcational aneurysm. These aneurysms may be positioned centrally on the ACoA or be decentred on one of the two A1–A2 corners and that determine the necessity to protect one or both anterior cerebral arteries during the coiling. Another critical point is the presence of symmetrical A1 segments: the hypoplasia of one of these two segments underlines the necessity of a monolateral approach. RT with a balloon through the ACoA, X-stenting (Fig. 5) and Y-stenting in case of hypoplasia of one of the two A1 segments and parallel stenting (two stents positioned from A1 to A2 in both sides) may be useful techniques and should be used depending on the operators’ experience. However, the use of balloon in small arteries, such as the ACoA, may expose to higher risk of over-inflation and consequent rupture of the aneurismal neck and prolonged occlusions may determine ischemic complications secondary to the hypoperfusion of perforating arteries (recurrent artery of heubner).
4. Pharmacological aspects in intracranial stenting According to cardiological protocols, a dual antiplatelet therapy is usually administered when a stent is placed intracranially. Patients treated with stent-assisted coiling or FDs receive a pretreatment (at least 7–10 days before in our clinical experience) with Clopidogrel 75 mg/day or Ticlopidine 250 mg (2 tablets/day), ASA 300 mg/day and gastric protector 1 tablet/day (Lansoprazole in most cases) considering all known cross-reactions [21]. Platelet inhibition may be evaluated with in vitro tests that calculate the residual platelet activity and the specific individual response to Thyenopiridines (Clopidogrel or Ticlopidine, correct values for a good platelet inhibition should be <70%) or to ASA (good results if residual platelet function is <20%) one or 2 days before the procedure. This algorithm may reduce the risk to release a stent in potential non-responder patients. Furthermore, another critical issue is the length of the dual antiplatelet therapy. Our experience suggested us to maintain a dual antiplatelet therapy for 6 months when a FD stent or at least two overlapping stents (Y- or X-stenting, telescopic stenting) are released to prevent the risk of ischemic complications secondary to the early suspension of one of the antiplatelet drugs (usually Thyenopiridines), probably due to longer times of re-endothelization of the stents. A 3 months therapy may be considered sufficient in those procedures in which a single stent is used. However, no certain data are present and further studies should be carried out to assess the most adequate dose and length of the pharmacological therapy.
5. Recanalization aneurysm rate for the EVT Aneurysm rest and recurrence are two important technical limits of EVT. The magnitude and clinical significance of these drawbacks are now well-known and embolized-patients need to have a longer follow-up compared to clipped patients [22]. Patients with ruptured aneurysm have a higher incidence of recurrence rate compared to patients affected by unruptured aneurysm. Nguyen et al. found a recanalization rate of 53.5% in the ruptured aneurysms versus 22.5% for unruptured aneurysms (p = 0.001) requiring a re-treatment by either re-coiling (with or without stent/balloon assistance) or surgical clipping [23]. This different finding between ruptured and unruptured aneurysm patients is due to a different morphology of the aneurysm wall. The wall of ruptured aneurysms is fragile compared to that of unruptured aneurysms. Histological analysis has shown that unruptured aneurysms are more likely to have thick intimalike walls than ruptured aneurysms which are more likely to have thin degenerate walls with hyaline deposits. Frosen et al. [24,25] postulate that the inflammatory response with infiltration of macrophages and T-cells as well as smooth muscle cell proliferation may have been present prior to rupture leading to wall instability. Multiple factors can influence the recanalization rate such as the used technique (coiling alone, balloon remodeling, coiling + stenting), the coiling-packing, the size and the site of aneurysm, and the type of devices used (opened or closed stents + coiling, flow diversion stent). Coiling technique has a higher incidence of recurrence rate, estimated up to 33.6% of cases, but there is no significant difference between aneurysms treated with complex coils only and those treated with helical ones [22,26]. Incomplete aneurysm occlusion with residual neck or aneurysm, has been identified as a significant predictor of recurrence. Moret et al. found that an initial incomplete occlusion conferred a higher risk of recurrence, especially in the group of
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Fig. 3. Pre-treatment angiographic assessment of a 9 × 7 mm unruptured MCA aneurysm in working projections (a and b). Microcatheterization of the superior branch of the MCA and initial deployment of the stent (Enterprise stent 4.5 × 37, Codman Neurovascular, J&J, Raynham, Massachusetts). Another microcatheter is already within the sac (c, jailing technique). Navigation within the other bifurcational branch through the first stent and subsequent deployment of the second one (Enterprise stent 4.5 × 28, Codman Neurovascular, J&J, Raynham, Massachusetts) (d). Coiling of the sac with Y-stenting (e). Final angiographic evaluation showing the complete occlusion of the sac (f).
aneurysms with larger dimensions. One interpretation is that complete obliteration of the lesion is important to decrease the number of early recurrences, and this can be achieved more frequently with technical advances, such as the use of complex coils or the balloon remodeling technique or stenting + coiling [26]. Technical advances, such as closed cell stenting + coiling, for unruptured cerebral aneurysms assure a lower incidence of recurrence, reduced to 10%, with a re-treatment rate to 5.8% [27].
The durability of endovascular coil occlusion of intracranial aneurysms is thought to depend on density of packing achieved within the aneurysm sac, commonly known as volumetric percentage occlusion (VPO) [28]. According to the “coiling-packing grade”, Moret et al. [26] did not find a significantly different numbers of recurring lesions between patients with a packing <24% and ≥24%, treated with “standard” bare-platinum coils.
Fig. 4. Pre-treatment DSA (Digital Subtraction Angiography) evaluation of a 6 × 5 mm aneurysm of the MCA bifurcation in working projections (a–b). Positioning of two remodeling balloons (2 Hyperglide 4 × 15, ev3-Covidien, Irvine, California) within both bifurcational branches (c). Kissing balloon assisted-coiling (d). Final 3D-DSA evaluation with subtracted images (e). Final angiogram at the end of the procedure (f).
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Fig. 5. Pre-treatment angiographic evaluation of an unruptured 5 mm aneurysm of the ACoA in frontal view (a). Positioning of two microcatheters (Prowler Select Plus 90◦ , Codman Neurovascular, Raynham, Massachusetts) for stent delivery (Enterprise stent 4.5 × 28 and 4.5 × 22, Codman Neurovascular, J&J, Raynham, Massachusetts) crossing through the ACoA, directed from A1 to the contralateral A2 segment of the ACA: the “X-shape” (b). Coiling of the sac after the deployment of the two stents (c). Final angiograms at the end of the procedure in frontal (d) and lateral (e) view showing the complete occlusion of the sac. 3D-DSA evaluation without subtracted images showing the reconstruction of the anatomy of the ACoA.
The hydrogel-coated coils (HydroCoils) embolization, a platinum coils covered with a hydrophilic polymer that swells in blood, seems to achieve a greater aneurysm packing density with decreased coil length with lower recurrence and retreatment rates. In fact, Gaba et al. [29] found a lower aneurysm recurrence rates (17%) at 1 year follow-up in fifty aneurysms embolized primarily using HydroCoils compared with 57 volumeand shape-matched aneurysms treated with standard platinum coils. Mascitelli et al. [30] achieved a statistically significant greater packing density (36.8%) with fewer coils compared with “conventional” coils using the Penumbra Coil 400 System, a new generation of softer platinum coils with a larger diameter than conventional embolic coils, registering, at 1 year follow-up, a lower recurrence rate. The larger diameter with the inherent softness of the coils should result in a higher packing density of coils within aneurysms that is marketed as having up to 400% more volume per unit length than conventional embolic coils. Large aneurysms (>10 mm) treated with coils have a greater propensity to recur than do smaller aneurysms [22]. According to the site of aneurysms, basilar bifurcation, ophthalmic carotid artery, anterior communicating artery, posterior communicating artery and MCA bifurcation, the recurrence rate is respectively up to 39.4%, 26.0%, 25.0%, 37.2% and 32.1% [22,31]. The incidence of recurrence could be reduced by the introduction of new generation stent: The Flow Diverter stent (FD). They have the property of forming high-coverage mesh on the neck of the aneurysm to reduce the blood flow into the sac, and subsequently to induce the aneurysm thrombosis, all while preserving the patency of adjacent small vessels. In fact, Berge et al. [32] found a complete aneurysm occlusion, without any recurrence, in 84% of cases. While Pistocchi et al. [33] found that fifteen of 19 aneurysms (78.9%) treated with FDs against 4 of 4 of aneurysms (100%) treated with FDs and coils were occluded with no angiographic recurrence of initially totally occluded aneurysms.
6. Conclusions The life cycle of aneurysms is a complex process with multiple actors where the flow dynamics play a key role in the process. The treatment of UIAs remains complex and not clearly defined. The endovascular treatment may be considered a safe and effective approach of unruptured intracranial aneurysms, considering the technical developments that allow the complete occlusion of the aneurismal sac also in challenging situations, such as the bifurcational aneurysms. These encouraging results, comparable to surgical series, remark the advantage of a minimally invasive treatment, although some issues, such as the correct selection of the patients in terms of indication to treat, the length of the followup and the pharmacological protocols still remain debated and in some cases controversies. Conflict of interest None. References [1] Raymond J, Kotowski M, Darsaut TE, Molyneux AJ, Kerr RS. Ruptured aneurysms and the International Subarachnoid Aneurysm Trial (ISAT): what is known and what remains to be questioned. Neuro-Chirurgie 2012;58(2–3):103–14. [2] Molyneux AJ, Kerr RS, Yu LM, et al. International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet 2005;366(9488):809–17. [3] Ohkuma H, Fujita S, Suzuki S. Incidence of aneurysmal subarachnoid hemorrhage in Shimokita, Japan, from 1989 to 1998. Stroke 2002;33:195–9. [4] Hijdra A, Braakman R, van Gijn J, Vermeulen M, van Crevel H. Aneurysmal subarachnoid hemorrhage. Complications and outcome in a hospital population. Stroke 1987;18(6):1061–7. [5] ISUIA Investigators. Unruptured intracranial aneurysms: risks of rupture and risks of surgical intervention. The New England Journal of Medicine 1998;339:1725–33.
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