Eleven patients harboring a total of nineteen lesions completed the imaging study and were included in the image analysis protocol. An additional eight patients were enrolled in the imaging study but excluded from final analysis: six patients were unable to complete the study secondary to severe anxiety or contraindication to MRI; an additional two patients completed the imaging protocol but were not included in imaging analysis due to significant motion artifact and poor image quality. No enrolled patients had adverse events related to ferumoxytol infusion. summarizes patient demographics, aneurysm characteristics, and imaging findings. is a flow chart summarizing the two protocols used in this pilot study.
Patient demographics, aneurysm characteristics, and imaging findings.
A flow chart illustrating the two protocols used for intracranial aneurysms.
Of the aneurysm patients who completed the study, five patients harbored large or giant (≥13mm) unruptured intracranial aneurysms. The second of these patients (subject 2) suffered aneurysm rupture approximately 12 hours following her baseline MRI and ferumoxytol injection. She was able to complete the study and thus her post-infusion images represent ruptured status. An additional six patients with smaller (<13mm) aneurysms completed the study.
A total of ten patients underwent aneurysm tissue analysis: five patients, who received ferumoxytol infusion, completed the imaging protocol, and subsequently had their aneurysm tissue analyzed following elective microsurgical clipping; and five patients (three with ruptured aneurysms and two with unruptured aneurysms) who served as controls and had their aneurysm tissue collected for analysis following microsurgical clipping.
Intracranial Aneurysm Imaging Findings
Nineteen aneurysms in 11 patients were imaged and analyzed. Two were giant aneurysms (≥25mm), four were large aneurysms (13≤ × <25mm) and thirteen were smaller (<13mm). In imaging Protocol A (imaging at baseline and 24hrs post-infusion of 2.5 mg/kg ferumoxytol), six patients with ten aneurysms were imaged. In this group, both giant aneurysms (subjects 1 and 2) were noted to have definite large magnitude ferumoxytol-associated loss of signal intensity within the aneurysm wall. One large aneurysm (subject 3) was noted to have a moderate amount of ferumoxytol-associated loss of signal intensity within the aneurysm wall. Two small aneurysms (subjects 5 and 6) had moderate signal change. One smaller aneurysm (subject 3) was judged by one neuroradiologist to have a definite small amount of ferumoxytol-associated loss of signal intensity within the aneurysm wall, while the second reviewing neuroradiologist felt that the aneurysm wall could not be adequately assessed due to confounding visualization of the contrast agent (ferumoxytol) within the arterial (and aneurysm) lumen (). In the remaining four aneurysms (one large, three smaller - subjects 3 and 4) no ferumoxytol-associated loss of signal intensity was appreciated (). In Protocol B, first stage (imaging at baseline, immediately post-infusion, 24-, 72- and 120-hrs post infusion of 5 mg/kg of ferumoxytol) two patients with four aneurysms were imaged. All of these aneurysms (one large and three small) had well defined ferumoxytol-associated loss of signal intensity within the aneurysm wall, more pronounced at 72 hours post infusion than at 24 hours post-infusion. At 120 hours post-infusion the signal change was notably diminished. This led to modifying Protocol B to a second stage: imaging at baseline, immediately post-infusion and 72 hours post-infusion. In this stage, three patients with a total of five aneurysms (one large and 4 small) were imaged. Three aneurysms (one large and two small) showed clear evidence of ferumoxytol-associated loss of signal intensity within the aneurysm wall at 72 hours post infusion. Two small aneurysms in this group did not show uptake of ferumoxytol at 72 hours post-infusion.
Protocol A: Anterior communicating artery aneurysm. Reviewer 1 rated small amount of ferumoxytol-associated signal change in aneurysm wall, while reviewer 2 did not appreciate any uptake within the aneurysm wall. (subject 3)
Protocol A: Right internal carotid artery terminus aneurysm. Both reviewers agreed to rate this aneurysm as: no ferumoxytol uptake within the aneurysm wall (subject 3)
Overall, of the nineteen aneurysms reviewed by our two neuroradiologists, there was a lack of agreement for only one aneurysm. Using simply “the percentage of agreement” to calculate the inter-observer agreement, then one would calculate that to be 95%. If we use Kappa (κ) measurement of agreement, then the inter-observer calculated agreement will be 89%.
Intracranial Aneurysm Tissue Analysis Findings
Ten patients underwent aneurysm tissue analysis. Five were patients with unruptured aneurysms who received ferumoxytol infusion and completed the imaging protocol. CD68+ and Prussian Blue stains were both positive in all five of these aneurysms. While double staining was not technically feasible, co-localization was utilized to verify presence of iron particles within macrophages cytoplasm localized only to the adventitial layer of the aneurysm wall. No nanoparticles were seen in the extracellular matrix and/or outside the cells in the tissues analyzed. Also no particles were seen at the interface of the intra-aneurysmal blood and the inner surface of the aneurysm dome. In the remaining five (control) patients who did not receive ferumoxytol nor undergo the imaging protocol (two with unruptured aneurysms and three with ruptured aneurysms), CD68 was positive (indicating presence of macrophages) and Prussian Blue stain was negative (indicating absence of iron particle, ferumoxytol) in all five aneurysms.