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

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Abstract

Introduction

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.

Methods

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.

Results

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 ± 1 vs. 3.58 ± 0.8, p = 0.02) and mean NTBI (7.39 ± 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.

Conclusions

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.

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Acknowledgments

The authors wish to thank Prof. Loav Cabantchik (Hebrew University of Jerusalem, Israel) for his guidance with the NTBI and REDOX-Fe tests. The authors wish to acknowledge the assistance provided with statistical analysis by Esteban Walker, PhD (Department of quantitative health sciences, Cleveland Clinic. Cleveland, OH), and Dr. Jennifer Frontera for her help with selection of statistical software. We also wish to thank Valerie Swank for her assistance with sample processing. This study was supported by a grant from the Cerebrovascular Center, Cleveland Clinic. Cleveland, OH, USA.

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Authors and Affiliations

  1. Cerebrovascular Center, Cleveland Clinic, Lerner Coll. Med./CWRU, 9500 Euclid Ave., S-80, Cleveland, OH, 44195, USA

    Joao A. Gomes

  2. Stroke Center, Beth Israel Deaconess Med. Ctr./Harvard Medical School, Boston, MA, USA

    Magdy Selim

  3. Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    Anne Cotleur

  4. Cerebrovascular Center, Cleveland Clinic, Cleveland, OH, USA

    M. Shazam Hussain, Gabor Toth, Khaled Asi & J. Javier Provencio

  5. Department of Neurology, Cleveland Clinic, Cleveland, OH, USA

    Lauren Koffman

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  1. Joao A. Gomes
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Correspondence to Joao A. Gomes.

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Gomes, J.A., Selim, M., Cotleur, A. et al. Brain Iron Metabolism and Brain Injury Following Subarachnoid Hemorrhage: iCeFISH-Pilot (CSF Iron in SAH). Neurocrit Care 21, 285–293 (2014). https://doi.org/10.1007/s12028-014-9977-8

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