Acta Neuropathologica

, 116:371 | Cite as

The pathology of superficial siderosis of the central nervous system

  • Arnulf H. Koeppen
  • Susan C. Michael
  • Danhong Li
  • Zewu Chen
  • Matthew J. Cusack
  • Walter M. Gibson
  • Simone V. Petrocine
  • Jiang Qian
Original Paper


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.


Axons Central nervous system Ferritin Heme Heme-oxygenase-1 Hemosiderin Iron Siderosis 



The laboratory work was performed in the facilities of the Research Service at the Veterans Affairs Medical Center in Albany, NY, USA, and X-Ray Optical Systems, East Greenbush, NY, USA. The authors have received financial assistance from Neurochemical Research, Inc., Glenmont, NY, USA, and the Department of Veterans Affairs, Washington, DC, USA. High-definition X-ray fluorescence work at X-Ray Optical Systems was supported by grant No. R44RR022001 from the National Center for Research Resources of the National Institutes of Health, Bethesda, MD, USA.


  1. 1.
    Ainsworth SK, Karnovsky MJ (1972) An ultrastructural staining method for enhancing the size and electron opacity of ferritin in thin sections. J Histochem Cytochem 20:225–229PubMedGoogle Scholar
  2. 2.
    Chen Z, Gibson WM, Huang H (2008) High definition X-ray fluorescence (HD XRF): principles and techniques. X-Ray Opt Instrum vol 2008. doi: 10.1155/2008/318171
  3. 3.
    Fearnly JM, Stevens JM, Rudge P (1995) Superficial siderosis of the central nervous system. Brain 118:1051–1066. doi: 10.1093/brain/118.4.1051 CrossRefGoogle Scholar
  4. 4.
    Gamble HJ (1967) Observations upon the human filum terminale. J Anat 101:631–632Google Scholar
  5. 5.
    Gamble HJ (1971) Electron microscope observations upon the conus medullaris and filum terminale of human fetuses. J Anat 110:173–179PubMedGoogle Scholar
  6. 6.
    Hintze KJ, Theil EC (2005) DNA and mRNA elements with complementary responses to hemin, antioxidant inducers, and iron control ferritin-L expression. Proc Natl Acad Sci USA 102:15048–15052. doi: 10.1073/pnas.0505148102 PubMedCrossRefGoogle Scholar
  7. 7.
    Hintze KJ, Katoh Y, Igarashi K, Theil EC (2007) Bach 1 repression of ferritin and thioredoxin reductase 1 is heme-sensitive in cells and in vitro and coordinates expression with heme oxygenase 1, β-globin, and NADP(H) quinone (oxido) reductase 1. J Biol Chem 282:34365–34271. doi: 10.1074/jbc.M700254200 PubMedCrossRefGoogle Scholar
  8. 8.
    Hughes JT, Oppenheimer DR (1969) Superficial siderosis of the central nervous system. Acta Neuropathol 13:56–74. doi: 10.1007/BF00686141 PubMedCrossRefGoogle Scholar
  9. 9.
    Koeppen AHW, Barron KD (1971) Superficial siderosis of the central nervous system. A histological, histochemical and chemical study. J Neuropathol Exp Neurol 30:448–469. doi: 10.1097/00005072-197107000-00010 PubMedCrossRefGoogle Scholar
  10. 10.
    Koeppen AH, Dentinger MP (1988) Brain hemosiderin and superficial siderosis of the central nervous system. J Neuropathol Exp Neurol 47:249–270. doi: 10.1097/00005072-198805000-00005 PubMedCrossRefGoogle Scholar
  11. 11.
    Koeppen AH, Borke RC (1991) Experimental superficial siderosis of the central nervous system. I. Morphological observations. J Neuropathol Exp Neurol 50:579–594. doi: 10.1097/00005072-199109000-00005 PubMedCrossRefGoogle Scholar
  12. 12.
    Koeppen AH, Dickson AC (2002) Tin-protoporphyrin prevents experimental superficial siderosis in rabbits. J Neuropathol Exp Neurol 61:689–701PubMedGoogle Scholar
  13. 13.
    Koeppen AH, Hurwitz CG, Dearborn RE, Dickson AC, Borke RC, Chu RC (1992) Experimental superficial siderosis of the central nervous system: biochemical correlates. J Neurol Sci 112:38–45. doi: 10.1016/0022-510X(92)90129-9 PubMedCrossRefGoogle Scholar
  14. 14.
    Koeppen AH, Dickson AC, Chu RC, Thach RE (1993) The pathogenesis of superficial siderosis of the central nervous system. Ann Neurol 34:646–653. doi: 10.1002/ana.410340505 PubMedCrossRefGoogle Scholar
  15. 15.
    Koeppen AH, Dickson AC, Smith J (2004) Heme oxygenase in experimental intracerebral hemorrhage. The beneficial effect of tin-mesoporphyrin. J Neuropathol Exp Neurol 63:587–597PubMedGoogle Scholar
  16. 16.
    Koeppen AH, Michael SC, Knutson MD, Haile DJ, Qian J, Levi S et al (2007) The dentate nucleus in Friedreich’s ataxia: the role of iron-responsive proteins. Acta Neuropathol 114:163–173. doi: 10.1007/s00401-007-0220-y PubMedCrossRefGoogle Scholar
  17. 17.
    Kumar N, Cohen-Gadol AA, Wright RA, Miller GM, Piepgras DG, Ahlskog JE (2006) Superficial siderosis. Neurology 66:1144–1152. doi: 10.1212/01.wnl.0000208510.76323.5b PubMedCrossRefGoogle Scholar
  18. 18.
    Levy M, Gurtz C, Llinás RH (2007) Superficial siderosis: a case report and review of the literature. Nat Clin Pract Neurol 3:54–58. doi: 10.1038/ncpneuro0356 PubMedCrossRefGoogle Scholar
  19. 19.
    Lin J-J, Daniels-McQueen S, Gaffield L, Walden WE, Thach RE (1990) Specificity of the induction of ferritin synthesis by hemin. Biochim Biophys Acta 1050:146–150PubMedGoogle Scholar
  20. 20.
    Matz PG, Massa SM, Weinstein PR, Turner C, Panter SS, Sharp FR (1996) Focal hyperexpression of hemeoxygenase-1 protein and messenger RNA in rat brain caused by cellular stress following subarachnoid injections of lysed blood. J Neurosurg 85:892–900PubMedCrossRefGoogle Scholar
  21. 21.
    Michael SC, Petrocine SV, Qian J, Lamarche JB, Knutson MD, Garrick MD et al (2006) Iron and iron-responsive proteins in the cardiomyopathy of Friedreich’s ataxia. Cerebellum 5:257–267. doi: 10.1080/14734220600913246 PubMedCrossRefGoogle Scholar
  22. 22.
    Milhorat TH, Hammock MK (1983) Cerebrospinal fluid as reflection of internal milieu of brain. In: Wood JH (ed) Neurobiology of cerebrospinal fluid, vol 2. Plenum Press, New York, pp 1–23Google Scholar
  23. 23.
    Nguyen-Legros J, Bizot J, Bolesse M, Pulicani JP (1980) Noir de diaminobenzidine: Une nouvelle méthode histochimique de révélation du fer exogène. Histochemistry 66:239–244. doi: 10.1007/BF00495737 PubMedCrossRefGoogle Scholar
  24. 24.
    Ogawa K, Sun J, Taketani S, Nakajima O, Nishitani C, Sassa S et al (2001) Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach 1. EMBO J 20:2835–2843. doi: 10.1093/emboj/20.11.2835 PubMedCrossRefGoogle Scholar
  25. 25.
    Rasmussen AT (1940) Studies of the VIIIth cranial nerve of man. Laryngoscope 50:67–83. doi: 10.1288/00005537-194001000-00008 CrossRefGoogle Scholar
  26. 26.
    Srisook K, Kim C, Cha Y-N (2005) Molecular mechanisms involved in enhancing HO-1 expression: de-repression by heme and activation by NrF2, the “one-two” punch. Antioxid Redox Signal 7:1674–1687. doi: 10.1089/ars.2005.7.1674 PubMedCrossRefGoogle Scholar
  27. 27.
    Sun J, Hoshino H, Takaku K, Nakajkima O, Muto A, Suzuki H et al (2002) Hemoprotein Bach 1 regulates enhancer availability of heme oxygenase-1 gene. EMBO J 21:5216–5224. doi: 10.1093/emboj/cdf516 PubMedCrossRefGoogle Scholar
  28. 28.
    Tarlov IM (1937) Structure of the nerve root. I. Nature of the junction between the central and peripheral nervous system. Arch Neurol Psychiatry 37:555–583Google Scholar
  29. 29.
    Triggs WJ, Wilmore LJ (1984) In vivo lipid peroxidation in rat brain following intracortical Fe2+ injection. J Neurochem 42:976–980. doi: 10.1111/j.1471-4159.1984.tb12699.x PubMedCrossRefGoogle Scholar
  30. 30.
    White K, Munro HN (1988) Induction of ferritin subunit synthesis by iron is regulated at both transcriptional and translational levels. J Biol Chem 263:8938–8942PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Arnulf H. Koeppen
    • 2
    • 3
    • 4
    • 6
  • Susan C. Michael
    • 2
  • Danhong Li
    • 5
  • Zewu Chen
    • 5
  • Matthew J. Cusack
    • 5
  • Walter M. Gibson
    • 5
  • Simone V. Petrocine
    • 4
  • Jiang Qian
    • 1
    • 4
  1. 1.Neurology ServiceVA Medical CenterAlbanyUSA
  2. 2.Research ServiceVA Medical CenterAlbanyUSA
  3. 3.Department of NeurologyAlbany Medical CollegeAlbanyUSA
  4. 4.Department of PathologyAlbany Medical CollegeAlbanyUSA
  5. 5.X-Ray Optical Systems, Inc.East GreenbushUSA
  6. 6.Neurology and Pathology Services (127/113)VA Medical CenterAlbanyUSA

Personalised recommendations