Evolution of Flow-Diverter Endothelialization and Thrombus Organization in Giant Fusiform Aneurysms after Flow Diversion: A Histopathologic Study

Discussion

Fusiform aneurysms of the circle of Willis represent 3%–13% of all intracranial aneurysms, with most located in the posterior circulation.¹¹ Their etiology is unclear; both atherosclerosis and dissection have been proposed as pathogenetic factors.¹² Some may present with subarachnoid hemorrhage, and these are generally considered dissecting aneurysms.¹³ Others may grow very large or giant and become symptomatic via neural compression or ischemia. The clinical course is generally progressive and, without successful treatment, almost always devastating.

Treatment options are limited. Drake and Peerless¹⁴ reported the results of 120 patients surgically treated for GFAs. Seventy-six percent of these patients with an anterior circulation GFA had a good outcome, whereas only 67% of those with a vertebrobasilar aneurysm had a good outcome. The treatment mostly included parent artery occlusion. In a more recent series, 6 of 9 symptomatic lesions resulted in poor outcomes (1 with bypass surgery, 1 with attempted clipping, and 4 with no intervention). Only those for whom parent artery occlusion was feasible fared well.¹⁵

Among the endovascular techniques, parent artery occlusion remains the best option for those with good collateral circulation.¹⁶ Reconstructive endovascular techniques, including FD-supported coiling or double-FD implantation, have been successfully applied for smaller fusiform aneurysms^17,18 but not for giant ones.

The introduction of FDs raised enthusiasm regarding reconstructive treatment of hardly treatable intracranial aneurysms, including GFAs. Fiorella et al^19⇓–21 reported 4 such patients successfully treated by FD implantation and coil packing. However, these publications were soon followed by reports on late complications, including late thrombosis of the FD within 2 years.⁹ Of 13 delayed ruptures after FD treatment reported by Kulcsár et al,²² 4 were in patients with a GFA. In a series by Siddiqui et al,¹⁰ after FD treatment for posterior circulation GFAs in 7 patients, 4 patients died and 2 had a poor outcome.

This study was undertaken to investigate potential reasons for such poor results, particularly when compared with the better outcomes achieved in patients with saccular aneurysms, even when those aneurysms were large or giant.¹ In general, the low efficacy of coil packing in giant aneurysms is attributed to the inability of the coils to induce permanent thrombosis and endothelial lining of the neck. In such lesions, thrombus organization and neck endothelialization were not found 2–6 months after treatment with coils.²³ FDs are expected to initially induce aneurysm thrombosis by intra-aneurysmal flow reduction and to seal the aneurysm cavity off from the circulation by inducing neointimal coverage of the FD surface at the neck. This seal would allow the intrasaccular thrombus to be eventually organized. In animal models, neointimal lining of the PED has been demonstrated as early as 7 days after implantation in normal arterial sections and 4–8 weeks after treatment across the neck of saccular aneurysms.^24,25 Studies on the endothelialization of FDs in human subjects have not been reported yet. We hypothesized that the reason for the poor results in GFAs was the lack of thrombus organization inside the aneurysm, the lack of intimal coverage of the FD, or both. Thrombus organization was expected to be visualized in the form of smooth muscle cell invasion and connective tissue formation within the clot.²⁶ Intimal growth over the luminal surface of the FD device was expected to be seen as a tissue layer consisting of smooth muscle cells covered by endothelium.

The design of the FD did not seem to make any difference. Two types were used, and each diameter was chosen to match the diameter of the normal artery proximal and distal to the fusiform dilation as closely as possible. Because of the fusiform nature of the aneurysms, all the FDs were fully opened and reached their nominal diameter inside the aneurysm. Subsequently, the device-to-vessel diameter ratio did not affect the final metal coverage, which is supposed to be approximately 30% for each device. The Surpass device had higher pore attenuation than the PED (20–32 and 15–22 pores/mm², respectively), but that did not influence the histologic outcome up to 9 months after treatment (On-line Table 1, patient 4).

The wall of the nonthrombosed control aneurysm contained a thick layer of smooth muscle cells consistent with myointimal hyperplasia.²⁷ In contrast, the walls of all treated aneurysms were fragmented with low cell attenuation, signs of inflammation, and a lack of smooth muscle cells. Inside the GFAs, there were no signs of smooth muscle cell invasion or connective tissue formation indicating clot organization, regardless of the length of follow-up (for as long as 13 months) and regardless of occlusion or patency of the aneurysm as seen on angiography. Clinical experience and experimental evidence have shown that the loss of mural cells is associated with an inability to transform intraluminal thrombus to stable scar tissue because of the lack of smooth muscle cells inside the wall.²⁸ Subsequently, the lack of thrombus organization is likely to be related to cellular loss of the sick wall in our GFAs.

All the treated aneurysms were partially thrombosed before treatment, which is likely to be the reason for their wall degeneration. The release of thrombocyte-derived growth factors and peroxidases from the luminal thrombus, together with deoxygenation of stagnating red blood cells and a subsequent lack of oxygen, are supposed to trigger cell death and inflammation inside the wall.²⁷ FDs may significantly reduce flow velocity within the aneurysm but cannot repair the aneurysm wall and facilitate clot organization because of the pre-existing lack of necessary smooth muscle cells. In fact, the stagnation induced by the FD may trigger further release of substances, such as matrix metalloproteinases, that damage the aneurysmal wall and increase the risk of rupture.^22,29

Histology showed lack of thrombus organization, which was consistent with MR imaging findings, which showed no change in signal intensity or size of the aneurysms during the follow-up period. Considering that simultaneous angiography showed partial or complete occlusion of the aneurysm and reconstruction of the parent artery, one must keep in mind that nonfilling of an aneurysm by angiography indicates only that blood is not flowing inside the aneurysm any more, but it certainly does not indicate healing of the aneurysm.

Intimal coverage is necessary for preventing FD thrombosis without aggressive antiplatelet medication. In our patients, only the section of FD implanted within the normal parent artery and circumferentially covered by normal arterial wall got covered by neointima and endothelialized as early as 6 months (patient 3). The portion of the FD inside the GFA without any contact with normal vascular wall remained uncovered, and no endothelial cells were found at any time point inside the aneurysms for as long as 13 months after treatment. This finding is similar to the lack of endothelialization seen in aortic FD grafts.³⁰ Although this is a typical characteristic of fusiform aneurysms, the same phenomenon may occur in giant aneurysms with very broad necks. Under such circumstances, any lack of sufficient platelet inhibition may result in either distal embolization or FD thrombosis.

Because histologic findings were similar in anterior and posterior fossa aneurysms, these phenomena are likely related to the fusiform morphology rather than the location of the aneurysms.

This work was limited by the small number of samples and warrants further experimental and clinical pathologic studies. High-resolution vessel wall imaging and sequential MR imaging of giant aneurysms after FD treatment may help us to understand more thoroughly the process of aneurysm thrombosis and the role of the aneurysm wall in the thrombotic process.