Caroline Helwick

May 01, 2013

New Orleans, Louisiana — The presence of macrophages within the walls of cerebral aneurysms, as shown by uptake of the iron oxide nanoparticle ferumoxytol, may herald instability and the probability of rupture within 6 months, results of a pilot study suggest.

"Our work is the first to point to molecular imaging of macrophages as a surrogate marker of inflammation, and a possible predictor of aneurysm rupture," said lead investigator David Hasan, MD, from University of Iowa Hospitals and Clinics in Iowa City.

Their early results in 22 patients were presented here at the American Association of Neurological Surgeons (AANS) 81st Annual Scientific Meeting.

Key Role

The wall of the cerebral aneurysm is rich in macrophages and inflammatory molecules, and inflammation is known to play a key role in aneurysm formation. This study evaluated the ability of MRI to identify macrophages within the walls of human cerebral aneurysms. MRI was enhanced with ferumoxytol, an ultrasmall superparamagnetic iron oxide nanoparticle that is taken up by macrophages.

"The clinical significance of early (ie, within the first 24 hours) uptake of ferumoxytol by macrophages in the wall of human cerebral aneurysms is not clear," Dr. Hasan told colleagues here during a Plenary Session. "The purpose of this study was to determine whether early uptake of ferumoxytol suggests an unstable cerebral aneurysm."

Thirty unruptured aneurysms in 22 patients were imaged 24 hours after infusion of ferumoxytol. Eighteen aneurysms were also imaged 72 hours after infusion of ferumoxytol. Aneurysm dome tissue was collected from 4 patients with early MRI signal changes, 5 patients with late signal changes, and 5 other patients with ruptured aneurysms. The tissue was immunostained for expression of cyclooxygenase (COX)-1, COX-2, microsomal prostaglandin E2 synthase-1 (mPGES-1), and macrophages.

"Immunostaining of the wall of these aneurysms showed uptake of ferumoxytol nanoparticles by the macrophages; therefore, we concluded that it is feasible to image these macrophages using ferumoxytol. We speculated that this shows active inflammation, and because of this an aneurysm could proceed to rupture," Dr. Hasan said.

In 23% (7 of 30) of the aneurysms, the investigators observed early uptake of ferumoxytol. Aneurysms were clipped in 4 of these patients and observed in 3 patients. All 3 of the conservatively managed aneurysms ruptured within 6 months, Dr. Hasan reported.

In 53% (16 of 30) of the aneurysms, uptake of ferumoxytol was observed late (ie, at 72 hours). Eight aneurysms were surgically clipped and 8 were managed conservatively; none ruptured or increased in size after 6 months.

Most aneurysms with late ferumoxytol uptake were 13 mm or smaller, whereas those with early uptake were of all sizes (ie, < 7 mm to > 25 mm).

The researchers further linked the presence of ferumoxytol uptake and also the rupturing of aneurysms to an inflammatory process. The expression of macrophages and the proinflammatory molecules COX-2 and mPGES-1 was similar between the unruptured aneurysms with early uptake of ferumoxytol and aneurysms that ruptured. Expression of these inflammatory molecules was also significantly higher in aneurysms with early uptake of ferumoxytol, they found.

"The proinflammatory molecules were markedly upregulated in the early signal group, and this was significantly different from the late group," he said. "We used to think that inflammation was a sequela of rupture, but we are showing that inflammation occurs prior to rupture and may be causing it."

"Our conclusion is that uptake of ferumoxytol in aneurysm walls within the first 24 hours strongly suggests aneurysm instability and may warrant urgent intervention," Dr. Hasan said. "We need a larger study, but prior to our work the only predictors of rupture were aneurysm size and location."

Study Too Small for Conclusions

Adel M. Malek, MD, PhD, who heads up the Cerebrovascular and Endovascular Division in the Department of Neurosurgery at Tufts University School of Medicine, Boston, Massachusetts, was the invited discussant of the paper. He maintained that the conclusions of the study were not fully supported by the evidence.

"This is an excellent pilot study, but the numbers are small, and the aneurysms with early ferumoxytol uptake that were observed and then ruptured were all large ( > 15 mm) or giant ( > 25 mm)," he pointed out.

"Based on only 3 aneurysms, their conclusion is a little strong," he said. "Furthermore, the study offers little data on the location and staining performed on the resected aneurysm dome tissue. Rupture is a very focal process. Where was the staining with respect to the uptake? Could early uptake represent wall changes that are unique to large or giant lesions?"

"Despite the study's limitations, the results are encouraging and consistent with other work," he noted. He said the findings should be validated in a multicenter study, especially with regard to outcomes in smaller aneurysms.

If the findings pan out, he added, "imaging of the aneurysm wall's inflammation state may offer the needed noninvasive metric to help stratify rupture risk and guide optimal decision-making."

Dr. Hasan and Dr. Malek have disclosed no relevant financial relationships.

American Association of Neurological Surgeons (AANS) 81st Annual Scientific Meeting. Abstract 705. Presented April 30, 2012.