How Flow Reduction Influences the Intracranial Aneurysm Occlusion: A Prospective 4D Phase-Contrast MRI Study

Flow Reduction and Thrombosis Outcomes

On average, the measured intra-aneurysmal velocities, Vel_an,pre = 21.7 ± 7.1 cm/s and Vel_an,post = 7.2 ± 2.9 cm/s, were in agreement with those in previous studies. On the basis of CFD simulations performed on 8 patients, Kulcsar et al¹⁶ reported time-averaged velocities reduced from 6 cm/s (pre-FDS) to 3 cm/s (post-FDS) for large aneurysms (diameter, >10 mm) and from 14.5  to 8 cm/s for small aneurysms (diameter, <10 mm). Consistent with our findings, Sindeev et al²⁰ showed a wide range of systolic Vel_an,pre = 44–7 cm/s before stent placement, with in vitro 4D-PCMR measurements, which converged to a narrower range after stent placement (Vel_an,post = 7.6–4 cm/s).

Various CFD studies have reported correlations between flow changes and aneurysm thrombosis, but there has been disagreement regarding the hemodynamic criteria associated with fast aneurysm occlusion. For example, Mut et al¹⁷ found that an absolute threshold of mean aneurysm velocity (1.3 cm/s), mean aneurysm inflow rate (0.37 mL/s), and mean shear rate (16.3 seconds⁻¹) discriminated between fast and slow occlusion times in a group of 23 aneurysms. By contrast, Kulcsar et al¹⁶ suggested a relative aneurysm-specific velocity and wall shear stress reduction threshold associated with thrombosis. Similarly, Ouared et al²⁵ found that a relative velocity reduction of at least one-third was associated with durable thrombosis. The hemodynamic component is widely accepted as the driving factor in aneurysm healing. This has led to a trend by manufacturers toward decreasing stent porosity by increasing the mesh density, while keeping reasonable navigation features and from the operator’s side, by adding stent layers to achieve “sufficient” contrast agent stagnation following subjective indicators considered prone to thrombosis patterns.²⁶

In this study, the PVRR was gradually lower in the 6- to 12-month thrombosis and no-thrombosis groups. This finding is consistent with a diminished flow reduction for delayed occlusions. However, the small PVRR differences among the 3 groups put in perspective the role of flow reduction as a driving parameter in the long-term occlusion of aneurysms treated by FDS. Other parameters should be also considered for a comprehensive understanding of IA thrombosis as suggested by the following studies: Paliwal et al¹⁸ showed that the average velocity reduction was not different between successful (52.4%) and unsuccessful (49.2%) treatments in 15 patients. Similarly, Berg et al²⁷ studied 2 morphologically equivalent carotid-ophthalmic aneurysms presenting with completely different outcomes (3-month occlusion for one and 3 additional layers required for the other) and found opposite hemodynamic changes. Furthermore, histologic studies suggest that neck endothelialization plays an important role in the healing process, highlighting the importance of stent wall apposition to promote the tissue growing across the neck.²⁸ Nevertheless, it remains unclear whether the aneurysm thrombosis, the neck endothelialization, or both are dominant factors for occlusion. Most interesting, Kadirvel et al²⁹ suggested that long-term occlusion occurred only as a result of neck covering, characterized by a contiguous layer of endothelial cells overlying a smooth-muscle cell substrate. This suggestion could bring new insights for manufacturers, researchers, and clinicians with implications for device development (Marosfoi et al³⁰ showed that temporal and spatial endothelial growth was related to stent design), adjunctive medications (Li et al³¹ showed that intravenous injection of recombinant human SDF-1-α accelerated re-endothelialization of the stent), and dual-antiplatelet therapy.

PCMR Measurements and Flow Diversion

This study was made possible due to prior investigations on intracranial stent–related artifacts.²³ In particular, we showed that these artifacts were mainly related to the shielding effect and were therefore restricted to the stent lumen. Furthermore, the following recent technical developments²⁴ were assembled in a postprocessing pipeline to obtain consistent and reliable PVRR and Vel_an assessment from 4D-PCMR data: 1) the combination of 4D-PCMR data with 3DRA geometry for a precise delineation of the circulating domain; 2) the partial volume correction allowing unbiased ICA mean flow-rate quantification; and 3) the semiautomatic aneurysm extraction, thus ensuring a systematic and user-independent selection of the volume of interest and the consistent inclusion of the relevant aneurysm inflow velocities close to the neck.³² In the context of flow-diversion treatment, only a few PCMR investigations have been reported. The hemodynamic changes in the parent vessel were measured in patients with 2D-PCMR by Eker et al⁷ and MacDonald et al.³³ Sindeev et al²⁰ used 4D-PCMR in 3 patient-specific models and found flow reductions of 89% and 30%–50% for fast and delayed thrombosis outcomes, respectively. Karmonik et al²¹ used a combination of in vitro experiments and the measurements of 3 patients, but these were not associated with occlusion times, findings similar to those of Pereira et al.²²

This limited literature can probably be attributed to the inherent limitations of 4D-PCMR related to data acquisition: long scan duration; coarse spatial resolution regarding the size of the IA; the unique velocity encoding (VENC) that cannot cover the large range of involved velocities; and the low temporal resolution, which smooths out the peak systolic velocities. Additionally, 4D-PCMR cannot provide mechanical loads, such as wall shear stress obtained with CFD simulations. However, simulations have their own restrictions: The patient flow conditions are usually unknown; the non-Newtonian behavior of the flow is rarely taken into account, though non-negligible for low velocities and recirculation areas as in flow diversion³⁴; and the virtual stent hardly replicates the actual procedure deployment and its related vessel-geometry modifications.³⁵ In comparison, 4D-PCMR has the great advantage of providing direct in vivo flow measurement readily available in clinical settings and already routinely applied for the hemodynamic assessment of cardiac disorders.³⁶ In the context of intracranial measurements, further improvements are needed to address the spatial resolution issues, while reducing the scanning time.

Clinical Relevance

The PVRRs of patients implanted with 2 stents were homogeneously distributed along the PVRR range (Fig 2C), with 1 having even the lowest value. Even if all the patients with double layers had occlusion at 6 months, the absence of a relationship between multilayer implantations and higher PVRRs suggests that the placement of additional devices does not necessarily increase the flow diversion. These results are in line with those of Chalouhi et al,³⁷ who demonstrated similar occlusion rates for single and multiple PED FDSs. Moreover, they showed that the placement of additional stent layers added only morbidity with a 3-fold complication rate. In our study, the wide range of velocities before stent placement (probably related to the wide range of aneurysm sizes and shapes) was dampened in a narrower range after stent implantation, independent of the initial conditions. From a clinical point of view, this is relevant information for interventionists to potentially avoid adding unnecessary stent layers.

Limitations

Our study has some limitations. First, whereas a range of VENC values has been used in the literature, we chose a VENC of 80 cm/s in accordance with Markl et al³⁸ for intracranial vessel measurements. Other 4D-PCMR studies used, VENCs of 120 cm/s,³⁹ 100 cm/s,²⁰ and a range of 60–80 cm/s²¹ for pre- and poststent acquisitions. Our main limitation, with a potential impact on the results, was the choice of the poststent VENC, which led us to decrease this parameter from 80 cm/s (the first 17 patients) to 40 cm/s (in the remaining 6 patients) to capture the low velocities more accurately at the expense of aliasing artifacts. Furthermore, to rely on the aneurysmal velocities presented in this study, we used the cutoff published in Pereira et al²² and Bouillot et al²³ to exclude patients with >50% of their prestent velocities below this value, assuming that poststent measurements would be severely biased. For some patients, the proportion of aneurysm volume below this threshold could have been larger than 50% after stent placement, thus reflecting very low velocities or nearly stagnant flows. This sensitive acquisition parameter would need to be refined by using in vitro ground truth measurements, such as particle imaging velocimetry, especially for poststent measurements.

Second, poststent MR imaging measurements were performed shortly after the procedure and did not reflect the entire IA thrombosis evolution influencing both the flow conditions and the neck endothelialization as shown in vitro by Gester et al.⁴⁰ Consequently, our statements should be weighed carefully, and further studies should be considered to monitor aneurysmal velocity modification during follow-up imaging. Third, our results presented here (based on systolic velocity reduction) are limited among other relevant flow parameters in flow diversion, such as wall shear stress, the stagnation zone, and residence time. The inherent limitations of the PCMR technique (spatial and temporal resolution) must be considered to accurately resolve near-wall velocities and low velocity ranges. Further research is needed to improve PCMR measurements to allow a reliable computation of these hemodynamic parameters. Finally, the small number of patients, especially for 12-month thrombosis time and thrombosis absence, may have limited the emergence of a significant relationship between PVRR and thrombosis time. The inaccuracy of low-velocity measurements could have also affected the low PVRRs. A study with a larger sample size would help in confirming the PVRR as a potential predictor for fast and delayed thrombosis.