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Flow diversion for intracranial aneurysms

Mudassar Kamran 
James V Byrne
Oxford Neurovascular and
Neuroradiology Research Unit, 
Nuffield Department of Surgical Sciences,
University of Oxford, UK
An aneurysm is a focal dilatation of a blood vessel caused by a complex interplay of factors, chief of which are the morphological characteristics of the vessel wall and local blood flow dynamics. Aneurysms of the intracranial vasculature are common, occurring in 0.5–6.0% of the general population.(1) Most intracranial aneurysms either remain asymptomatic and undetected or are discovered incidentally on neuroimaging studies; only a small proportion are brought to medical attention as a result of aneurysm-related symptoms. The most devastating clinical presentation is spontaneous intracranial haemorrhage, that is, subarachnoid haemorrhage (SAH). This type of stroke carries a fatality rate of 32–67% and a long-term dependence rate of 10–20%.(1) The management goals are to prevent the first episode of aneurysmal bleed for unruptured aneurysms and, for ruptured aneurysms, to secure the aneurysm against re-bleed.
Principles of treatment
The underlying treatment principle is to exclude the aneurysmal sac from the circulation. Treatment techniques have evolved since Walter Dandy’s first successful surgical clipping of an intracranial aneurysm in 1937. Minimally invasive endovascular treatments are alternatives to neurosurgical clipping and became popular following the introduction of electrolytically detachable platinum coils by Guglielmi in 1990.(2) Endosaccular packing of aneurysm with metal coils and the consequent thrombosis completely obliterates the aneurysm in most cases. However even after successful treatment, the structurally weak vascular segment that gave rise to the aneurysm in the first place remains exposed to the same unfavourable local haemodynamic forces. The durability of endosaccular coil embolisation (ECE) of aneurysms is thus a major concern. 
Fusiform shape, complex morphology, large size, and wide neck aneurysms are difficult to treat by ECE and are likely to have high recurrence rates. In a systematic review of 8161 patients undergoing ECE, Ferns and colleagues reported adequate post-treatment aneurysmal occlusion in 91.2% of cases,(3) but on long-term follow up, 20.5% of the coiled aneurysms showed re-opening and 10.3% required re-treatment. From a theoretical standpoint, high recurrence rates observed after endosaccular coiling are related to its inability to effectively address the pathogenic factors underlying development of aneurysms, that is the structural vessel wall weakness (segmental or circumferential) and unfavourable local cerebral haemodynamics. 
Flow diversion – a new endovascular treatment 
To address the shortcomings of ECE outlined above, endoluminal stents with low porosity were introduced as an alternative endovascular treatment. These stents, popularly known as flow diverters (FD), are deployed in the parent vessel across the neck of aneurysms with the aim of uncoupling blood flow between parent artery and aneurysm sac. The treatment goals with FD are: to reconstruct the parent vessel, repairing any segmental or circumferential vessel wall defects that lead to the origin and progression of the aneurysm; and to redirect blood flow along the longitudinal axis of the parent vessel, thereby modifying the haemodynamic forces acting on the aneurysm.(4) Once deployed, the flow diverter creates a physical barrier across the neck of aneurysms disrupting blood flow into and out of the aneurysm. The barrier introduced by the FD is augmented by the growth of endothelium and a neointima on its inner surface, promoting stagnation and thrombosis of blood inside the sac. Endosaccular thrombosis may take several weeks to develop and can be followed on angiographic imaging. Endothelialisation of the FD, once achieved, marks complete reconstruction of the parent vessel–aneurysm complex, effectively excluding the aneurysm from the circulation and modifying the culprit pathogenic factors.(5)
Technical specifications 
The essential feature of a stent designed to induce aneurysm thrombosis by disrupting saccular inflow and outflow is its low effective porosity achieved by higher metal content. The first flow diversion prosthesis made available for clinical use was the SILK flow diverter (SFD; Balt Extrusion, Montmorency, France). It received the European Community (CE) mark in January 2008 and can be used with or without endosaccular coils. 
The other is Pipeline Embolism Device (PED; ev3; Chestnut Medical), which also has a CE mark and was approved by the US Food and Drug Administration in 2011.
The SFD is a flexible, self-expanding, braided mesh stent with flared ends and a pore size of 110–250μm (Figure 1). Constructed from 48 braided nitinol (nickel–titanium alloy) and platinum microfilaments ~35μm, SFD provides 35–55% metal coverage at its nominal diameter.(6)  Currently available SILK Plus is the newest generation FD that covers a range of diameters (3–5.5mm) and lengths (15–40mm) and are equipped with multiple radiopaque markers to allow adequate visualisation under fluoroscopy.(7) The PED is similar and is constructed of 48 microfilaments of platinum and nickel-cobalt-chromium alloy.
The SFD is retrievable and repositionable in cases where the initial positioning is not ideal. Endosaccular coils can be placed before the stent is deployed or afterwards via a second microcatheter positioned prior to SFD deployment, a technique often referred to as ‘jailing’.(7) 
Preliminary clinical results 
Several reports on the technical feasibility, safety, and efficacy of FDs have been published. An overview of these results is provided in Table 1, and the key findings and important issues are discussed below.
Since its introduction, more than 3000 aneurysms had been treated with the SFD by the end of 2011.(8) 
Occlusion of aneurysms
Byrne and colleagues conducted the first international multicentre registry exploring the safety and efficacy of SFD for treatment of intracranial aneurysms.(10) Data for 70 patients treated at 18 participating centres were evaluated for the device’s technical performance, and angiographic and clinical outcomes were measured (Table 1). The majority of procedures were performed using SFD alone (n = 60) whereas in a small proportion (n = 10) adjuvant coils were used. The registry highlighted promises and potential issues with the use of SFD, which may be applicable to the discussion of flow diversion treatment technique in general. The authors reported a high incidence of successful SFD deployment and progressive aneurysm occlusions, taking into account the preliminary use of the device.
Similar findings were reported after treatments with PED in the PITA trial (Pipeline Embolisation in the Intracranial Treatment of Aneurysms). Longer follow-up in this study and the PUFS study (Pipeline for Uncoilable or Failed Aneurysms), which evaluated PED use in large, complex aneurysms, found six-month complete occlusion rates of 73.6% of PUFS and 93.3% in the PITA trial.
Importance of antiplatelet therapy
Another important issue highlighted by the early reports on flow diversion treatment is the use of antiplatelet therapy, and the trade off between preventing thromboembolic complications (caused by blood clot forming on the stent) and the increased risk of bleeding (intracranial aneurysmal or extracranial bleeding).(9) In the acute setting after SAH, there is a natural reluctance to administer antiplatelet therapy until the ruptured aneurysm has been secured.  However, stent thrombosis prophylaxis is best given before the FD is deployed as its delayed administration increases the risk of thrombotic complications. How the antiplatelet therapy influences evolution of FD-induced aneurysmal thrombosis remains unclear. It may have a contributory role in symptomatic worsening consequent to aneurysmal sac swelling in the early post-treatment period and in the long-term, it may contribute to occurrence of delayed haemorrhage seen in a minority of patients. Both early and delayed aneurysmal ruptures after SFD treatment have been reported. 
Turowski and coworkers published the first report of early fatal haemorrhage after SFD treatment of a symptomatic, unruptured large paraophthalmic internal carotid artery aneurysm.(15) Post- treatment angiograms for this patient showed considerable reduction of intraneurysmal blood flow. On computed tomography (CT) images obtained 11 days post-treatment, the aneurysm was occluded except for a small area of hypodensity in the neck region. However, at 20 days post-procedure, the patient became comatose and CT scan demonstrated extensive SAH and an increase in the hypodensity seen on the earlier CT. Thus, the aneurysm thrombosis induced by FDs might not be as stable as that induced by ECE.
Adding coils into the aneurysmal sac?
It still remains unclear whether coils should be deployed in the sac to achieve optimal and fast aneurysm occlusion. Following a minority of late-hemorrhagic complications, some have suggested that adding coils might induce a faster positive thrombosis of the aneurysm and prevent late-rupture. In fact, there is no exhaustive evidence to support the need to use coils in combination with FD and the choice should, in our opinion, be left to individual preference, until data from trials become available.
The learning curve
Stenting, and in particular flow diversion, represents a revolution in the treatment of intracranial aneurysm. Identifying the appropriate indications of its use and acquisition of required operator skills are critical elements for its successful adoption. Even centres experienced in the use of intracranial endovascular devices need instruction, and treatment procedures should be monitored by experienced operators.
Prospective and randomised clinical trials 
So far, systematic study of the use of FDs is limited to non-comparative cohort studies. Randomised clinical trials have been proposed to compare it with conventional endovascular aneurysm treatments in a rigorous fashion. One prospective, randomised controlled trial of the SFD, called MARCO POLO (multicentre randomised trial on selective endovascular aneurysm occlusion with coils versus parent vessel reconstruction using the SILK FD), is underway. It has been designed to compare SFD treatment against ECE for efficacy (angiographic outcomes at 12 months post-procedure) and safety (technical problems and clinical complications in a 12 month period post-procedure). 
Similar ongoing trials of the PED evaluating the device’s technical and clinical performance are: (i) the FIAT trial, comparing clinical outcomes between flow diversion and best standard treatment (conservative, coiling, stenting, or parent artery occlusion methods); and (ii) the COCOA trial, comparing PED with coiling in small wide neck aneurysms.
Flow diversion is an attractive treatment alternative for patients with recurrent aneurysms after ECE or aneurysms with challenging morphology, that is, large or giant size, wide neck, or fusiform shape, which are difficult to treat by conventional coil embolisation and might have a high likelihood of recurrence. A thorough evaluation of the economic impact of flow diversion treatment is needed. Ongoing randomised clinical trials are expected to provide robust evidence on the techniques safety and efficacy.
  1. Johnston SC et al. Recommendations for the endovascular treatment of intracranial aneurysms. Stroke 2002;33 2536–44.
  2. Guglielmi G et al. Electrothrombosis of saccular aneurysms via endovascular approach. Part 2: Preliminary clinical experience. J Neurosurg 1991;75:8–14.
  3. Ferns SP et al. Coiling of intracranial aneurysms / supplemental appendix. Stroke 2009; 40:e523–9.
  4. D’Urso PI et al. Flow diversion for intracranial aneurysms. Stroke 2011;42:2363–68.
  5. Kamran M et al. Assessment of angiographic outcomes after flow diversion treatment of intracranial aneurysms: a new grading schema. Neuroradiology 2011;53:501–508.
  6. Kulcsár Z et al. High-profile flow diverter (Silk) implantation in the basilar artery. Stroke 2010;41:1690–96.
  7. Lubicz B et al. Flow-diverter stent for the endovascular treatment of intracranial aneurysms. Stroke 2010;41:2247–53.
  8. Kulcsár Z, et al. Intra-aneurysmal thrombosis as a possible cause of delayed aneurysm rupture after flow-diversion treatment. Am J Neuroradiol 2011;32:20–25.
  9. Byrne JV et al. Early experience in the treatment of intra-cranial aneurysms by endovascular flow diversion: a multicentre prospective study. PLoS ONE 2010 5:e12492.
  10. Wagner A et al. Treatment of  intracranial aneurysms. Reconstruction of the parent artery with flow-diverting (Silk) stent. Neuroradiology 2011. doi:10.1007/s00234-011-0949-9.
  11. Cirillo L et al. The use of  flow-diverting stents in the treatment of giant cerebral aneurysms: Preliminary results. Neuroradiol J 2010;23:220–24.
  12. Berge J et al. Perianeurysmal brain inflammation after flow-diversion treatment. Am J Neuroradiol 2011. doi:10.3174/ajnr.A2710.
  13. Kulcsár Z et al. Effect of flow diversion treatment on very small ruptured aneurysms. Neurosurgery 2010;67:789–93.
  14. Pumar JM et al. Vascular reconstruction of a fusiform basilar aneurysm with the Silk embolization system. J Neurointerv Surg 2010;2:242–44.
  15. Turowski B et al. Early fatal hemorrhage after endovascular cerebral aneurysm treatment with a flow diverter (SILK-Stent). Neuroradiology 2010;53: 37–41.