The pathology of superficial siderosis of the central nervous system
- 12 August 2008
- journal article
- research article
- Published by Springer Science and Business Media LLC in Acta Neuropathologica
- Vol. 116 (4), 371-382
- https://doi.org/10.1007/s00401-008-0421-z
Abstract
Chronic or intermittent extravasations of blood into the subarachnoid space, and dissemination of heme by circulating cerebrospinal fluid, are the only established causes of superficial siderosis of the central nervous system (CNS). We studied the autopsy tissues of nine patients by iron histochemistry, immunocytochemistry, single- and double-label immunofluorescence, electron microscopy of ferritin, and high-definition X-ray fluorescence. In one case, frozen brain tissue was available for quantitative assay of total iron and ferritin. Siderotic tissues showed extensive deposits of iron and ferritin, and infiltration of the cerebellar cortex was especially severe. In addition to perivascular collections of hemosiderin-laden macrophages, affected tissues displayed iron-positive anuclear foamy structures in the neuropil that resembled axonal spheroids. They were especially abundant in eighth cranial nerves and spinal cord. Double-label immunofluorescence of the foamy structures showed co-localization of neurofilament protein and ferritin but comparable merged images of myelin-basic protein and ferritin, and ultrastructural visualization of ferritin, did not allow the conclusion that axonopathy was simply due to dilatation and rupture of fibers. Heme-oxygenase-1 (HO-1) immunoreactivity persisted in macrophages of siderotic cerebellar folia. Siderosis caused a large increase in total CNS iron but high-definition X-ray fluorescence of embedded tissue blocks excluded the accumulation of other metals. Holoferritin levels greatly exceeded the degree of iron accumulation. The susceptibility of the cerebellar cortex is likely due to Bergmann glia that serve as conduits for heme; and the abundance of microglia. Both cell types biosynthesize HO-1 and ferritin in response to heme. The eighth cranial nerves are susceptible because they consist of CNS axons, myelin, and neuroglial tissue along their subarachnoid course. The persistence of HO-1 protein implies continuous exposure of CNS to free heme or an excessively sensitive transcriptional response of the HO-1 gene. The conversion of heme iron to hemosiderin probably involves both translational and transcriptional activation of ferritin biosynthesis.Keywords
This publication has 28 references indexed in Scilit:
- High Definition X-Ray Fluorescence: Principles and TechniquesX-Ray Optics and Instrumentation, 2008
- Bach1 Repression of Ferritin and Thioredoxin Reductase1 Is Heme-sensitive in Cells and in Vitro and Coordinates Expression with Heme Oxygenase1, β-Globin, and NADP(H) Quinone (Oxido) Reductase1Published by Elsevier BV ,2007
- Superficial siderosis: a case report and review of the literatureNature Clinical Practice Neurology, 2007
- Iron and iron-responsive proteins in the cardiomyopathy of Friedreich's ataxiaThe Cerebellum, 2006
- Molecular Mechanisms Involved in Enhancing HO-1 Expression: De-Repression by Heme and Activation by Nrf2, The "One-Two" PunchAntioxidants and Redox Signaling, 2005
- Focal hyperexpression of hemeoxygenase-1 protein and messenger RNA in rat brain caused by cellular stress following subarachnoid injections of lysed bloodJournal of Neurosurgery, 1996
- The pathogenesis of superficial siderosis of the central nervous systemAnnals of Neurology, 1993
- In Vivo Lipid Peroxidation in Rat Brain Following Intracortical Fe2+ InjectionJournal of Neurochemistry, 1984
- AN ULTRASTRUCTURAL STAINING METHOD FOR ENHANCING THE SIZE AND ELECTRON OPACITY OF FERRITIN IN THIN SECTIONSJournal of Histochemistry & Cytochemistry, 1972
- Studies of the viiith cranial nerve of manThe Laryngoscope, 1940