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We report histopathological findings from a human cerebral aneurysm following treatment with a flow diverter. A 75-year-old male underwent flow diversion treatment (Pipeline Embolization Device (PED)) and coil embolization for treatment of an aneurysm at the basilar tip. At four months, angiography showed complete aneurysm occlusion; at 12 months angiography demonstrated that the aneurysm had reopened. The patient expired from brainstem compression. The aneurysm cavity was primarily filled with unorganized thrombus. Thick, interrupted neointima crossed the neck interface indicating blood flow into aneurysm through small channels. Along the parent artery the PED was covered by neointima having a measured thickness of 0.19±0.01mm; the maximal stenosis of the proximal parent artery was 27%. The perforating arteries that were crossed by the PED remained patent. Findings in this human case are similar to those in the elastase-induced aneurysms in rabbits.
Flow diversion devices represent an important advance in aneurysm treatment, but there remains very little data regarding histologic response to these devices in humans.1 Substantial preclinical work using the elastase-induced aneurysm model in rabbits showed high rates of aneurysm occlusion, mild degrees of parent artery stenosis, and uniform patency of branch vessels following implantation of flow diverters.2–6 Angiographic findings in clinical series have, in general, mimicked the preclinical outcomes.7,8 We herein report the detailed histopathological response flowing pipeline treatment for a human cerebral aneurysm.
A 75-year-old male presented with progressive neurological deterioration after diagnosis secondary to brainstem compression from a basilar apex aneurysm. The aneurysm measured 14.5mm in width and 15.5mm in length. Conventional angiography (Figure 1(a)) verified the aneurysm presence. The patient underwent treatment with a single Pipeline Embolization Device (PED, eV3, Irvine, CA, USA), extending from the basilar artery to the right posterior cerebral artery (PCA). Angiography immediately after PED implantation demonstrated the aneurysm remained patent, but the contrast filling within the aneurysm cavity was decreased (Figure 1(b)). Follow-up angiography performed at one and three months after PED placement showed persistent filling of the aneurysm and patency of the PED construct (Figures 1(c) and ((d)).d)). The patient underwent coiling via a retrograde left posterior communicating artery catheterization, bypassing the PED, three months after PED placement. Follow-up angiography at four months post PED treatment demonstrated complete occlusion (Figure 1(e)). Eight months after PED treatment, magnetic resonance angiography (MRA) confirmed this occlusion but no regression of the thrombus mass within the aneurysm cavity. Twelve months after PED treatment, the patient had further neurological decline. MRA and angiography showed the aneurysm had reopened (Figure 1(f)). The patient subsequently expired from brainstem compression.
The aneurysm and implanted devices were harvested and fixed in 10% neutral buffered formalin for histopathological evaluation. After gross examination, the aneurysm and adjacent arteries underwent tissue processing and analysis using a modified histological technique.2 Axial tissue sections from proximal, mid-, and distal portions of the proximal artery (parent artery starting from basilar artery site to neck) were stained with hematoxylin and eosin (H&E). The morphometric measurements were performed. The internal elastic lamina area and luminal area were measured. Neointimal thickness was measured as the distance from the inner surface of each PED strut to the luminal border. Calculations made from the morphometric measurements were as follows: neointimal area=internal elastic lamina area − luminal area; percent stenosis=(injured luminal area/internal elastic lamina area)×100; mean injury score=sum of injury scores for each strut/number of struts; mean neointimal thickness=sum of neointimal thickness/number of struts.9 Tissue sections were immunostained for smooth muscle cells (smooth muscle cell actin (SMA))
A basilar tip aneurysm was present, which was filled with coil loops and dark tissue; the PED located within the distal part of the basilar artery crossed over the aneurysm neck and extended to the right PCA and was visible through the thin arterial wall (Figure 2(a)). The PED also crossed over several perforating arteries (Figure 2(b)) and a large focus of hemorrhage (3.0cm×2.0cm×3.0cm in measurement) was continuous up with the coiled part of the aneurysm (Figure 2(c)).
Microscopic examination showed the majority of the aneurysm cavity was filled with fresh, unorganized thrombus and coil loops (Figure 3(a)). The dome of the aneurysm was mainly filled with loose, hypocellular tissue. PED at the neck interface was covered with a thick layer of neointima (Figure 3(b)), which consisted of SMA positive cells (Figure 3(c)). This neointima bridged most of the neck interface. A small channel remained without neo-intimal coverage at the neck interface; this channel was filled with fresh blood clot and continued up to the aneurysm cavity and down to the parent artery lumen (Figure 3(d)). This finding demonstrated that the aneurysm did not completely occlude histologically and was still patent to the parent artery lumen.
The PED within the parent artery was covered with neointima (Figure 3(e)); the average neointimal thickness of the proximal parent artery (basilar artery) was measured to be 0.19±0.01mm; the maximal stenosis of the proximal parent artery was 27%.
There was no significant inflammatory reaction to the device.
Neointimal growth was observed at the origin of perforating artery branches that had the PED device across their ostia; this neointima at the ostia was interrupted and discontinuous (Figure 3(f)).
We performed histological examination on a human cerebral aneurysm treated with coils and PED. Results showed that PED placement in humans results in neointimal hyperplasia across the aneurysm neck interface and mild neointimal hyperplasia along the parent artery. Further, the ostia of small perforating arteries which had been crossed with the PED remained histologically patent up to 12 months after treatment with partial coverage with neointimal hyperplasia but continued flow through small channels. These findings are similar to those seen in the rabbit elastase-induced model.2,3
The histology of the aneurysm presented here is similar to aneurysms treated with platinum and matrix coils.10,11 In addition to providing information regarding the histologic response to flow diversion this case also represents a rare instance of apparent reopening of a completely occluded aneurysm, based on angiography, following PED treatment. However, the case is unusual in that PEDs serve as representatives of the current new generation of flow diversion devices. Clinical studies demonstrated that PEDs have many advantages over traditional coils and other stent types. These advantages include high complete occlusion rates with low complications,12,13 an effective alternative for large, wide-neck or giant aneurysms which are impossible to treat using standard endovascular or surgical techniques.13,14
To our knowledge, almost all of the high complete occlusion rates were based on angiography follow-up. No study showed the detailed tissue response to the new device in the human cerebral aneurysm, nor has any histology follow-up been reported so far. This is the first case which histologically addressed the tissue response along with the PED placement either at the neck or at the ostia of small branched arteries; also this is the first case which concluded the follow-up results from the histological view. As illustrated in this case report, angiography follow-up showed the aneurysm was occluded four months after PED placement (one month post coiling), but had reopened by 12 months.
Histologically, however, the aneurysm neck likely was never completely occluded. Relevance of this case is unclear regarding “typical” flow diversion treatments, as the aneurysm was at an arterial bifurcation and coil embolization was performed adjacent to the indwelling PED. We reported a detailed histological response following PED treatment in a human case; however, this is only one case. We cannot predict that all patients will have the same histological change following PED treatment.
Histologic response in human cerebral aneurysm following PED flow diversion device treatment was similar to those in the elastase-induced aneurysm in rabbit. The elastase-induced aneurysm model in rabbit is an appropriate model for testing new flow diversion devices.
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by National Institutes of Health grant NS 076491.