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Flow diverters and intracranial aneurysms

Laurent Pierot and Krzysztof Kadziolka
29 July, 2013  
Flow diverters are dense mesh stents used for the treatment of specific groups of intracranial aneurysms. The safety, efficacy and present use of these devices are discussed
Laurent Pierot MD PhD
Krzysztof Kadziolka MD
Department of Neuroradiology,
Hôpital Maison Blanche,
CHU Rheims, Faculté de Médecine de Rheims, Rheims, France
The prevalence of intracranial aneurysms in the population is high, that is, close to 3%.(1) The major risk of an intracranial aneurysm is its rupture, leading to intracranial bleeding (subarachnoid, parenchymal, and/or intraventricular hemorrhage). Aneurysm rupture is associated with a high case fatality (between 40% and 50%).(2)
After the initial aneurysm rupture, the aneurysm wall is fragile and a re-rupture with new bleeding can be observed, especially in the 15 days following the initial event. For this reason, in the case of rupture, early treatment of the aneurysm is mandatory. Historically, the first treatment was open surgery, with clipping of the aneurysm. A second therapeutic option was developed in the eighties and nineties with occlusion of the aneurysm through an endovascular approach. It is now the first-line treatment in the management of ruptured aneurysms.(3)
  
Aneurysms are sometimes discovered before any rupture. The treatment of such unruptured aneurysms is discussed, as the individual risk of bleeding is very difficult to evaluate. From large studies, the risk of rupture increases with aneurysm size and in some aneurysm locations (posterior circulation).(4) Subsequently the treatment strategy for patients with unruptured aneurysms is defined on an individual basis taking into account several factors including the patient’s age, the size of the aneurysm and its location.
Endovascular treatment of intracranial aneurysms: limits
The first endovascular approach used for the treatment of intracranial aneurysms was coiling. However, as differing types of aneurysm can be encountered according to their shape (sacciform/fusiform), size (small/large/giant) neck size (narrow/wide neck), location and physiopathology, this treatment soon faced limitations. Wide-neck and fusiform aneurysms are not easily treated with coils, which have a tendency to migrate into the parent vessel, with a risk of parent vessel occlusion.
The remodelling technique (temporary inflation of a balloon in front of the neck during deposition of the coils) was subs(5,6) An alternative treatment approach for wide-neck aneurysms was stenting.
Despite these technical developments, the endovascular treatment of intracranial aneurysms still has limitations. First, it is not always applicable to complex aneurysms, such as fusiform aneurysms or very large neck aneurysms. Second, even if the endovascular treatment of some complex aneurysms is now feasible using the remodeling technique or regular stenting, the long-term stability of aneurysm occlusion is not guaranteed in all aneurysms. Thus large and giant aneurysms, as well as large neck aneurysms, are candidates for aneurysm reopening (recanalisation).(7)
Flow diverters: conceptual basis
For the past 20 years, endovascular treatment has been focused on filling the aneurysm with coils. However, another approach is possible and theoretically more physiological: parent vessel reconstruction. Flow diverters are dedicated to this type of approach.(8)
  • Flow diverters are stents with a very dense mesh. The aim of flow diverter treatment is primarily to reconstruct the diseased vascular segment harbouring the saccular or fusiform aneurysm pouch. The device used for parent vessel reconstruction produces haemodynamic and biological effects including:
  • Flow redirection: the flow diverter crosses the aneurysm neck and diverts the blood flow from the aneurysm sac, thus reducing shear stress on the aneurysm wall and promoting intra-aneurysm flow stasis and thrombosis. This phenomenon is affected by the amount of metal surface area coverage provided by the stent. 
Tissue overgrowth: the flow diverter provides a scaffolding for the development of endothelial and neointimal tissue across the aneurysm neck. 
Devices
Two devices are currently included in the flow diverter group:
Pipeline embolisation device (PED, EV3-MTI, Irvine, CA) is a self-expanding, flexible, cylindrical mesh-like device, composed of 25% platinum tungsten and 75% cobalt chromium, made from 48 strands interwoven in a standard pattern. The PED has a diameter of between 2.5 and 5mm and a length of between 10 and 35 mm (Figure 1).
Silk (Balt, Montmorency, France) is a self-expanding stent made of 48 braided nitinol strands. 
Feasibility and safety of aneurysm treatment with flow diverters
In preliminary series dealing with PED, the treatment was always feasible.(9,10)  With the Silk stent, failures were encountered in a limited number of cases (4–10%)(11,12)
The safety of flow diverters is difficult to precisely evaluate owing to the small series of patients currently published in the literature (1–70 patients). The results are heterogeneous from one series to another; series are dealing with complex aneurysms, making comparison with series with regular aneurysms difficult; also these first series are describing preliminary experience during the ascending phase of the learning curve. So larger series are certainly needed to allow precise assessment.
Preliminary series with PED showed good safety with very low morbidity and mortality.(9,10) In one series using the Silk stent, the procedural morbidity was low (1.4%), but delayed morbidity and mortality were more frequent, leading to an overall morbidity (including procedural) of 4% and a mortality of 8%.(11) In another Silk series, mortality and morbidity rates were 4% and 15%, respectively.(12) 
One important issue concerning the treatment of intracranial aneurysms using flow diverters is the patency of the perforating arteries and side branches covered by the device. In most cases, side branches covered by the device are patent after the procedure and in the long-term. Occlusion of small perforators arteries is possible and was singularly observed in basilar artery aneurysms.(13)
A number of papers have documented the occurrence of delayed aneurysm rupture after flow diversion treatment. Kulcsar et al reported 13 delayed ruptures after Silk treatment. Patients were separated into two groups with early and late ruptures.(14) Early rupture (
Mechanisms of delayed rupture are actually not elucidated completely. A haemodynamic mechanism can play a role, the sudden change in flow pattern leading to increased stress in areas of the aneurysm not previously exposed to strain.  Another potential mechanism involves intra-aneurysmal thrombosis created by flow diversion, which can be associated with an inflammatory reaction and the weakening of the aneurysm wall. Anti-aggregation may also play a role, thereby preventing platelet aggregation before and during aneurysm rupture.
Several methods have been proposed to prevent delayed aneurysm rupture after flow diversion: aneurysm filling with coils; increase of the flow-diverting effect of the implants; and steroid administration just after aneurysm treatment.
Efficacy of flow diverters
According to the current series published in the literature, the treatment of intracranial aneurysms with flow diverters is associated with a high rate of complete aneurysm occlusion.(9–12)
However, it is important to note that the evolution of aneurysm occlusion is quite different between flow diverters and coils. When an aneurysm is treated by selective occlusion using coils, a thrombus will rapidly occur in the aneurysm sac and protection against bleeding or re-bleeding is obtained rapidly, except in the case of incomplete occlusion. By contrast, with a flow diverter a complete occlusion is rarely obtained at the end of the procedure but is frequently observed during the follow-up after three to six months (49–95%). The process of aneurysm occlusion after flow diverter treatment is certainly linked, in part, to the administered antiplatelet regimen.
Perioperative medications
Perioperative medications are important in the management of intracranial aneurysms with flow diverters because there are competing risks of thromboembolic complications, including in-stent thrombosis and delayed aneurysm rupture. 
Patients are generally treated with heparin during the procedure, which is then discontinued at the end of the procedure.
Pre-medication with antiplatelet agents is given for one to five days before the endovascular intervention. The most frequent pre-treatment is based on a combination of aspirin (100–325mg) and clopidogrel (75–300mg). Higher doses (320mg aspirin and 300mg clopidogrel) were used when the pre-treatment period was short (one day). Clopidogrel is sometimes replaced by dipyridamole.
In most cases, a double antiplatelet treatment (either aspirin + clopidogrel or aspirin + dipyridamole) was given for six weeks to six months after the procedure, followed by a single antiplatelet agent, usually aspirin.
Present indications
The precise indications of flow diversion are not yet precisely established. In the series published in the literature, flow diverters were mainly used in large and giant aneurysms, wide-neck aneurysms, and recurrent aneurysms. A small series has suggested the value of flow diversion treatment in very small aneurysms untreatable by standard coiling technique.
Studies in progress
Several studies, including randomised trials, are currently underway. They will provide more precise information regarding safety and efficacy of flow diversion for treating intracranial aneurysms with respect to standard endovascular techniques (balloon-assisted or stent-assisted coiling). Robust clinical investigations will also provide information concerning the treatment indications for difficult-to-treat complex aneurysms, as well as non-complex aneurysms.
Conclusions
The treatment of intracranial aneurysms with flow diverters seems to be highly efficacious. According to preliminary series, safety is satisfactory, specifically in the context of treating complex aneurysms. However, the frequency and the mechanism of delayed rupture after flow diversion must be analysed in order to precisely define the indications of this technique, the appropriate perioperative medications, and the way the treatment is performed (additional coiling or not). The current indications for the use of flow diverters are complex aneurysms, including large and giant aneurysms, wide neck aneurysms, and aneurysm recurrences. Flow diverters have also been proposed for use in very small ruptured aneurysms that are untreatable using standard endovascular techniques.
A number of studies, including randomised trials, are underway and will contribute to a more precise knowledge regarding indications and results of flow diversion techniques.
References
  1. Vlak MHM et al. Prevalence of unruptured intracranial aneurysms with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. Lancet Neurol 2011;10:626–36.
  2. Niewcamp DJ et al. Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region : a meta-analysis. Lancet Neurol 2009;8:635–42.
  3. Molyneux AJ et al. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet 2002;360:1262–3.
  4. ISUIA Investigators. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 2003;362:103–10.
  5. Pierot L et al. Endovascular treatment of unruptured intracranial aneurysms: comparison of safety of remodeling technique and standard treatment with coils. Radiology 2009;251:846–55.
  6. Pierot L et al. The remodelling technique for endovascular treatment of ruptured intracranial aneurysms had a higher rate of adequate occlusion than did conventional coil embolization with comparable safety. Radiology 2011;258: 546–53.
  7. Ferns SP et al. Coiling of intracranial aneurysms: a systematic review on initial occlusion and reopening and retreatment rates. Stroke 2009;40:e523–29.
  8. Pierot L. Flow diverters stents in the treatment of intracranial aneurysms: Where are we? J Neuroradiol 2011;38:40–46.
  9. Lylyk P et al. Curative endovascular reconstruction of cerebral aneurysms with the pipeline embolization device: The Buenos Aires experience. Neurosurgery 2009;4:632–43.
  10. Szikora I et al. Treatment of intracranial aneurysms by functional reconstruction of the parent artery: The Budapest experience with the Pipeline Embolization Device. AJNR Am J Neuroradiol 2010;31:1139–47.
  11. Byrne JV et al. Early experience in the treament of intra-cranial aneurysms by endovascular flow diversion: A multicentre prospective study. PloS One 2010;5:1–8.
  12. Lubicz B et al. Flow-diverter stent for the endovascular treatment of intracranial aneurysms. A prospective study in 29 patients with 34 aneurysms. Stroke 2010;41:2247–53.
  13. Kulcsar Z et al. High-profile flow diverter implantation in the basilar artery: efficacy in the treatment of aneurysms and the role of perforators. Stroke 2010; 41:1690–6.
  14. Kulcsar Z et al. Intraaneurysmal thrombosis as a possible cause of delayed aneurysm rupture after flow diversion treatment. AJNR Am J Neuroradiol 2011;32:20–25.