Brain Iron Metabolism and Brain Injury Following Subarachnoid Hemorrhage: iCeFISH-Pilot (CSF Iron in SAH)

Iron-mediated oxidative damage has been implicated in the genesis of cerebral vasospasm in animal models of SAH. We sought to explore the relationship between levels of non-protein bound iron in cerebrospinal fluid and the development of brain injury in patients with aneurysmal SAH. Patients admitted with aneurysmal subarachnoid hemorrhage to a Neurointensive care unit of an academic, tertiary medical center, with Hunt and Hess grades 2-4 requiring ventriculostomy insertion as part of their clinical management were included in this pilot study. Samples of cerebrospinal fluid (CSF) were obtained on days 1, 3, and 5. A fluorometric assay that relies on an oxidation sensitive probe was used to measure unbound iron, and levels of iron-handling proteins were measured by means of enzyme-linked immunosorbent assays. We prospectively collected and recorded demographic, clinical, and radiological data. A total of 12 patients were included in this analysis. Median Hunt and Hess score on admission was 3.5 (IQR: 1) and median modified Fisher scale score was 4 (IQR: 1). Seven of 12 patients (58 %) developed delayed cerebral ischemia (DCI). Day 5 non-transferrin bound iron (NTBI) (7.88 +/- A 1 vs. 3.58 +/- A 0.8, p = 0.02) and mean NTBI (7.39 +/- A 0.4 vs. 3.34 + 0.4 p = 0.03) were significantly higher in patients who developed DCI. Mean redox-active iron, as well as day 3 levels of redox-active iron correlated with development of angiographic vasospasm in logistic regression analysis (p = 0.02); while mean redox-active iron and lower levels of ceruloplasmin on days 3, 5, and peak concentration were correlated with development of deep cerebral infarcts. Our preliminary data indicate a causal relationship between unbound iron and brain injury following SAH and suggest a possible protective role for ceruloplasmin in this setting, particularly in the prevention of cerebral ischemia. Further studies are needed to validate these findings and to probe their clinical significance.