Acta Neuropathologica

, Volume 123, Issue 6, pp 773–786 | Cite as

Saccular intracranial aneurysm: pathology and mechanisms

  • Juhana Frösen
  • Riikka Tulamo
  • Anders Paetau
  • Elisa Laaksamo
  • Miikka Korja
  • Aki Laakso
  • Mika Niemelä
  • Juha Hernesniemi
Review Article

Abstract

Saccular intracranial aneurysms (sIA) are pouch-like pathological dilatations of intracranial arteries that develop when the cerebral artery wall becomes too weak to resist hemodynamic pressure and distends. Some sIAs remain stable over time, but in others mural cells die, the matrix degenerates, and eventually the wall ruptures, causing life-threatening hemorrhage. The wall of unruptured sIAs is characterized by myointimal hyperplasia and organizing thrombus, whereas that of ruptured sIAs is characterized by a decellularized, degenerated matrix and a poorly organized luminal thrombus. Cell-mediated and humoral inflammatory reaction is seen in both, but inflammation is clearly associated with degenerated and ruptured walls. Inflammation, however, seems to be a reaction to the ongoing degenerative processes, rather than the cause. Current data suggest that the loss of mural cells and wall degeneration are related to impaired endothelial function and high oxidative stress, caused in part by luminal thrombosis. The aberrant flow conditions caused by sIA geometry are the likely cause of the endothelial dysfunction, which results in accumulation of cytotoxic and pro-inflammatory substances into the sIA wall, as well as thrombus formation. This may start the processes that eventually can lead to the decellularized and degenerated sIA wall that is prone to rupture.

Keywords

Aneurysm Intracranial Histopathology Pathophysiology Inflammation 

Notes

Acknowledgments

This work was supported by the research funds of The Helsinki University Central Hospital (EVO Grant TYH 2010209) and research grants from The Sigrid Juselius Foundation, Helsinki, Finland; The Maire Taponen Foundation, Helsinki, Finland; and The Biomedicum Helsinki Foundation, Helsinki, Finland.

References

  1. 1.
    Alikhani M, Alikhani Z, Raptis M et al (2004) TNF-a in vivo stimulates apoptosis in fibroblasts through caspase-8 activation and modulates expression of pro-apoptotic genes. J Cell Physiol 201:341–348PubMedCrossRefGoogle Scholar
  2. 2.
    Aoki T, Nishimura M (2011) The development and the use of experimental animal models to study the underlying mechanisms of CA formation. J Biomed Biotechnol 2011:535921PubMedCrossRefGoogle Scholar
  3. 3.
    Bavinzski G, Talazoglu V, Killer M et al (1999) Gross and microscopic histopathological findings in aneurysms of the human brain treated with Guglielmi detachable coils. J Neurosurg 9:284–293Google Scholar
  4. 4.
    Beck J, Rohde S, el Beltagy M et al (2003) Difference in configuration of ruptured and unruptured intracranial aneurysms determined by biplanar digital subtraction angiography. Acta Neurochir (Wien) 145:861–865CrossRefGoogle Scholar
  5. 5.
    Bor AS, Rinkel GJ, Adami J et al (2008) Risk of subarachnoid haemorrhage according to number of affected relatives: a population based case-control study. Brain 131:2662–2665PubMedCrossRefGoogle Scholar
  6. 6.
    Boyle J, Weissberg P, Bennett M (2003) Tumor necrosis factor-alpha promotes macrophage-induced vascular smooth muscle cell apoptosis by direct and autocrine mechanisms. Arterioscler Thromb Vasc Biol 23:1553–1558PubMedCrossRefGoogle Scholar
  7. 7.
    Bruno G, Todor R, Lewis I et al (1998) Vascular extracellular matrix remodeling in cerebral aneurysms. J Neurosurg 89:431–440PubMedCrossRefGoogle Scholar
  8. 8.
    Chapman AB, Rubinstein D, Hughes R et al (1992) Intracranial aneurysms in autosomal dominant polycystic kidney disease. N Engl J Med 327:916–920PubMedCrossRefGoogle Scholar
  9. 9.
    Chien S (2008) Effects of disturbed flow on endothelial cells. Ann Biomed Eng 36:554–562PubMedCrossRefGoogle Scholar
  10. 10.
    Chyatte D, Bruno G, Desai S et al (1999) Inflammation and intracranial aneurysms. Neurosurgery 45:1137–1146PubMedCrossRefGoogle Scholar
  11. 11.
    Cloft HJ, Kallmes DF, Kallmes MH et al (1998) Prevalence of cerebral aneurysms in patients with fibromuscular dysplasia: a reassessment. J Neurosurg 88:436–440PubMedCrossRefGoogle Scholar
  12. 12.
    Conway JE, Hutchins GM, Tamargo RJ (1999) Marfan syndrome is not associated with intracranial aneurysms. Stroke 30:1632–1636PubMedCrossRefGoogle Scholar
  13. 13.
    Fabriek BO, Dijkstra CD, van den Berg TK (2005) The macrophage scavenger receptor CD163. Immunobiology 210:153–160PubMedCrossRefGoogle Scholar
  14. 14.
    Ferns SP, Sprengers ME, van Rooij WJ et al (2009) Coiling of intracranial aneurysms: a systematic review on initial occlusion and reopening and retreatment rates. Stroke 40:e523–e529PubMedCrossRefGoogle Scholar
  15. 15.
    Fontaine V, Jacob MP, Houard X et al (2002) Involvement of the mural thrombus as a site of protease release and activation in human aortic aneurysms. Am J Pathol 161:1701–1710PubMedCrossRefGoogle Scholar
  16. 16.
    Frösen J, Piippo A, Paetau A et al (2004) Remodeling of saccular cerebral artery aneurysm wall is associated with rupture: histological analysis of 24 unruptured and 42 ruptured cases. Stroke 35:2287–2293PubMedCrossRefGoogle Scholar
  17. 17.
    Frösen J, Piippo A, Paetau A et al (2006) Growth factor receptor expression and remodeling of saccular cerebral artery aneurysm walls: implications for biological therapy preventing rupture. Neurosurgery 58:534–541PubMedGoogle Scholar
  18. 18.
    Frösen J, Marjamaa J, Myllärniemi M et al (2006) Contribution of mural and bone marrow-derived neointimal cells to thrombus organization and wall remodeling in a microsurgical murine saccular aneurysm model. Neurosurgery 58:936–944PubMedCrossRefGoogle Scholar
  19. 19.
    Frösen J, Litmanen S, Tulamo R et al (2006) Matrix metalloproteinase-2 and -9 expression in the wall of saccular cerebral artery aneurysm. Neurosurgery 58:413–413 (Conference abstract)Google Scholar
  20. 20.
    Frösen J (2006) The pathobiology of saccular cerebral artery aneurysm rupture and repair. A clinicopathological and experimental approach. Helsinki University Press. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/frosen/thepatho.pdf
  21. 21.
    Gieteling EW, Rinkel GJ (2003) Characteristics of intracranial aneurysms and subarachnoid haemorrhage in patients with polycystic kidney disease. J Neurol 250:418–423PubMedCrossRefGoogle Scholar
  22. 22.
    Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35PubMedCrossRefGoogle Scholar
  23. 23.
    Guo F, Li Z, Song L, Han T (2007) Increased apoptosis and cysteinyl aspartate specific protease-3 gene expression in human intracranial aneurysm. J Clin Neurosci 14:550–555PubMedCrossRefGoogle Scholar
  24. 24.
    Hashimoto N, Handa H, Hazama F (1978) Experimentally induced cerebral aneurysms in rats. Surg Neurol 10:3–8PubMedGoogle Scholar
  25. 25.
    Hashimoto N, Kim C, Kikuchi H (1987) Experimental induction of cerebral aneurysms in monkeys. J Neurosurg 67:903–905PubMedCrossRefGoogle Scholar
  26. 26.
    Hassler O (1961) Morphological studies on the large cerebral arteries, with reference to the aetiology of subarachnoid haemorrhage. Acta Psychiatr Scand Suppl 154:1–145PubMedGoogle Scholar
  27. 27.
    Heiskanen O (1989) Ruptured intracranial arterial aneurysms of children and adolescents. Surgical and total management results. Childs Nerv Syst 5:66–70PubMedCrossRefGoogle Scholar
  28. 28.
    Heiskanen O, Vilkki J (1981) Intracranial arterial aneurysms in children and adolescents. Acta Neurochir (Wien) 59:55–63CrossRefGoogle Scholar
  29. 29.
    Hessler JR, Morel DW, Lewis LJ et al (1983) Lipoprotein oxidation and lipoprotein-induced cytotoxicity. Arteriosclerosis 3:215–222PubMedCrossRefGoogle Scholar
  30. 30.
    Houard X, Ollivier V, Louedec L (2009) Differential inflammatory activity across human abdominal aortic aneurysms reveals neutrophil-derived leukotriene B4 as a major chemotactic factor released from the intraluminal thrombus. FASEB J 23:1376–1383PubMedCrossRefGoogle Scholar
  31. 31.
    Huttunen T, von und zu Fraunberg M, Frösen J et al (2010) Saccular intracranial aneurysm disease: distribution of site, size, and age suggests different etiologies for aneurysm formation and rupture in 316 familial and 1454 sporadic eastern Finnish patients. Neurosurgery 66:631–638PubMedCrossRefGoogle Scholar
  32. 32.
    Inci S, Spetzler RF (2000) Intracranial aneurysms and arterial hypertension: a review and hypothesis. Surg Neurol 53:530–540PubMedCrossRefGoogle Scholar
  33. 33.
    Ingall T, Asplund K, Mahonen M et al (2000) A multinational comparison of subarachnoid hemorrhage epidemiology in the WHO MONICA stroke study. Stroke 31:1054–1061PubMedCrossRefGoogle Scholar
  34. 34.
    Isaksen J, Egge A, Waterloo K et al (2002) Risk factors for aneurysmal subarachnoid haemorrhage: the Tromsø study. J Neurol Neurosurg Psychiatry 73:185–187PubMedCrossRefGoogle Scholar
  35. 35.
    Jamous MA, Nagahiro S, Kitazato KT (2007) Endothelial injury and inflammatory response induced by hemodynamic changes preceding intracranial aneurysm formation: experimental study in rats. J Neurosurg 107:405–411PubMedCrossRefGoogle Scholar
  36. 36.
    Jayaraman T, Berenstein V, Li X et al (2005) Tumor necrosis factor alpha is a key modulator of inflammation in cerebral aneurysms. Neurosurgery 57:558–564PubMedCrossRefGoogle Scholar
  37. 37.
    Juvela S, Poussa K, Porras M (2001) Factors affecting formation and growth of intracranial aneurysms: a long-term follow-up study. Stroke 32:485–491PubMedCrossRefGoogle Scholar
  38. 38.
    Juvela S, Poussa K, Porras M (2000) Natural history of unruptured intracranial aneurysms: probability of and risk factors for aneurysm rupture. J Neurosurg 93:379–387PubMedCrossRefGoogle Scholar
  39. 39.
    Kataoka K, Taneda M, Asai T et al (1999) Structural fragility and inflammatory response of ruptured cerebral aneurysms. A comparative study between ruptured and unruptured cerebral aneurysms. Stroke 30:1396–1401PubMedCrossRefGoogle Scholar
  40. 40.
    Kim C, Cervos-Navarro J, Kikuchi H et al (1993) Degenerative changes in the internal elastic lamina relating to the development of saccular cerebral aneurysms in rats. Acta Neurochir (Wien) 121:76–81CrossRefGoogle Scholar
  41. 41.
    Kim SC, Singh M, Huang J et al (1997) Matrix metalloproteinase-9 in cerebral aneurysms. Neurosurgery 41:642–666PubMedGoogle Scholar
  42. 42.
    Klos A, Tenner AJ, Johswich KO et al (2009) The role of the anaphylatoxins in health and disease. Mol Immunol 46:2753–2766PubMedCrossRefGoogle Scholar
  43. 43.
    Kondo S, Hashimoto N, Kikuchi H et al (1998) Apoptosis of medial smooth muscle cells in the development of saccular cerebral aneurysms in rats. Stroke 29:181–188PubMedCrossRefGoogle Scholar
  44. 44.
    Korja M, Silventoinen K, McCarron P et al (2010) Genetic epidemiology of spontaneous subarachnoid hemorrhage: Nordic Twin Study. Stroke 41:2458–2462PubMedCrossRefGoogle Scholar
  45. 45.
    Kosierkiewicz TA, Factor SM, Dickson DW et al (1994) Immunocytochemical studies of atherosclerotic lesions of cerebral berry aneurysms. J Neuropathol Exp Neurol 53:399–406PubMedCrossRefGoogle Scholar
  46. 46.
    Krischek B, Kasuya H, Tajima A et al (2008) Network-based gene expression analysis of intracranial aneurysm tissue reveals role of antigen presenting cells. Neuroscience 154:1398–1407PubMedCrossRefGoogle Scholar
  47. 47.
    Kurki MI, Häkkinen SK, Frösen J et al (2011) Upregulated signaling pathways in ruptured human saccular intracranial aneurysm wall: an emerging regulative role of Toll like receptor signaling and NF-KB, HIF1A and ETS transcription factors. Neurosurgery 68:1667–1676PubMedCrossRefGoogle Scholar
  48. 48.
    Laaksamo E, Tulamo R, Baumann M et al (2008) Involvement of mitogen-activated protein kinase signaling in growth and rupture of human intracranial aneurysms. Stroke 39:886–892PubMedCrossRefGoogle Scholar
  49. 49.
    Marchese E, Vignati A, Albanese A et al (2010) Comparative evaluation of genome-wide gene expression profiles in ruptured and unruptured human intracranial aneurysms. J Biol Regul Homeost Agents 24:185–195PubMedGoogle Scholar
  50. 50.
    Michel JB, Thaunat O, Houard X et al (2007) Topological determinants and consequences of adventitial responses to arterial wall injury. Arterioscler Thromb Vasc Biol 27:1259–1268PubMedCrossRefGoogle Scholar
  51. 51.
    Moestrup SK, Moller HJ (2004) CD163: a regulated hemoglobin scavenger receptor with a role in the anti-inflammatory response. Ann Med 36:347–354PubMedCrossRefGoogle Scholar
  52. 52.
    Moore KJ, Tabas I (2011) Macrophages in the pathogenesis of atherosclerosis. Cell 145:341–355PubMedCrossRefGoogle Scholar
  53. 53.
    Morimoto M, Miyamoto S, Mizoguchi A (2002) Mouse model of cerebral aneurysm: experimental induction by renal hypertension and local hemodynamic changes. Stroke 33:1911–1915PubMedCrossRefGoogle Scholar
  54. 54.
    Nagakawa H, Suzuki S, Haneda M (2000) Significance of glomerular deposition of C3c and C3d in IgA nephropathy. Am J Nephrol 20:122–128CrossRefGoogle Scholar
  55. 55.
    Nahed BV, Bydon M, Ozturk AK (2007) Genetics of intracranial aneurysms. Neurosurgery 60:213–225PubMedCrossRefGoogle Scholar
  56. 56.
    Newby AC, Zaltsman AB (2000) Molecular mechanisms in intimal hyperplasia. J Pathol 190:300–309PubMedCrossRefGoogle Scholar
  57. 57.
    Nielsen MJ, Moestrup SK (2009) Receptor targeting of hemoglobin mediated by the haptoglobins: roles beyond heme scavenging. Blood 114:764–771PubMedCrossRefGoogle Scholar
  58. 58.
    Nieuwkamp DJ, Setz LE, Algra A et al (2009) Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a metaanalysis. Lancet Neurol 8:635–642PubMedCrossRefGoogle Scholar
  59. 59.
    Nurden AT (2011) Platelets, inflammation and tissue regeneration. Thromb Haemost 105(Suppl 1):S13–S33PubMedCrossRefGoogle Scholar
  60. 60.
    Nyström SH (1963) Development of intracranial aneurysms as revealed by electron microscopy. J Neurosurg 20:329–337CrossRefGoogle Scholar
  61. 61.
    Pentimalli L, Modesti A, Vignati A et al (2004) Role of apoptosis in intracranial aneurysm rupture. J Neurosurg 101:1018–1025PubMedCrossRefGoogle Scholar
  62. 62.
    Pera J, Korostynski M, Krzyszkowski T et al (2010) Gene expression profiles in human ruptured and unruptured intracranial aneurysms: what is the role of inflammation? Stroke 41:224–231PubMedCrossRefGoogle Scholar
  63. 63.
    Pope FM, Nicholls AC, Narcisi P et al (1981) Some patients with cerebral aneurysms are deficient in type III collagen. Lancet 1:973–975PubMedCrossRefGoogle Scholar
  64. 64.
    Raghavan ML, Ma B, Harbaugh RE (2005) Quantified aneurysm shape and rupture risk. J Neurosurg 102:355–362PubMedCrossRefGoogle Scholar
  65. 65.
    Rinkel GJ, Djibuti M, Algra A et al (1998) Prevalence and risk of rupture of intracranial aneurysms: a systematic review. Stroke 29:251–256PubMedCrossRefGoogle Scholar
  66. 66.
    Ronkainen A, Hernesniemi J, Ryynanen M et al (1994) A ten percent prevalence of asymptomatic familial intracranial aneurysms: preliminary report on 110 magnetic resonance angiography studies in members of 21 Finnish familial intracranial aneurysm families. Neurosurgery 35:208–212PubMedCrossRefGoogle Scholar
  67. 67.
    Ronkainen A, Hernesniemi J, Ryynänen M (1993) Familial Subarachnoid Hemorrhage in East Finland, 1977–1990. Neurosurgery 33:787–797PubMedCrossRefGoogle Scholar
  68. 68.
    Rubinstein MK, Cohen NH (1964) Ehlers-Danlos syndrome associated with multiple intracranial aneurysms. Neurology 14:125–132PubMedCrossRefGoogle Scholar
  69. 69.
    Sakaki T, Kohmura E, Kishiguchi T et al (1997) Loss and apoptosis of smooth muscle cells in intracranial aneurysms. Studies with in situ DNA end labeling and antibody against single-stranded DNA. Acta Neurochir (Wien) 139:469–474CrossRefGoogle Scholar
  70. 70.
    Sandvei MS, Romundstad PR, Müller TB et al (2009) Risk factors for aneurysmal subarachnoid hemorrhage in a prospective population study: the HUNT study in Norway. Stroke 40:1958–1962PubMedCrossRefGoogle Scholar
  71. 71.
    Sawabe M (2010) Vascular aging: from molecular mechanism to clinical significance. Geriatr Gerontol Int 10(Suppl 1):S213–S220PubMedCrossRefGoogle Scholar
  72. 72.
    Scanarini M, Mingrino S, Giordano R et al (1978) Histological and ultrastructural study of intracranial saccular aneurysmal wall. Acta Neurochir (Wien) 43:171–182CrossRefGoogle Scholar
  73. 73.
    Scanarini M, Mingrino S, Zuccarello M et al (1978) Scanning electron microscopy (s.e.m.) of biopsy specimens of ruptured intracranial saccular aneurysms. Acta Neuropathol 44:131–134PubMedCrossRefGoogle Scholar
  74. 74.
    Schievink WI, Michels VV, Piepgras DG (1994) Neurovascular manifestations of heritable connective tissue disorders. A review. Stroke 25:889–903PubMedCrossRefGoogle Scholar
  75. 75.
    Schievink WI, Schaid DJ, Michels VV et al (1995) Familial aneurysmal subarachnoid hemorrhage: a community-based study. J Neurosurg 83:426–429PubMedCrossRefGoogle Scholar
  76. 76.
    Shojima M, Oshima M, Takagi K et al (2004) Magnitude and role of wall shear stress on cerebral aneurysm: computational fluid dynamic study of 20 middle cerebral artery aneurysms. Stroke 35:2500–2505PubMedCrossRefGoogle Scholar
  77. 77.
    Shojima M, Oshima M, Takagi K et al (2005) Role of the bloodstream impacting force and the local pressure elevation in the rupture of cerebral aneurysms. Stroke 36:1933–1938PubMedCrossRefGoogle Scholar
  78. 78.
    Soehnlein O, Weber C, Lindbom L (2009) Neutrophil granule proteins tune monocytic cell function. Trens Immunol 30:538–546CrossRefGoogle Scholar
  79. 79.
    Stegmayr B, Eriksson M, Asplund K (2004) Declining mortality from subarachnoid hemorrhage: changes in incidence and case fatality from 1985 through 2000. Stroke 35:2059–2063PubMedCrossRefGoogle Scholar
  80. 80.
    Stehbens WE (1963) Histopathology of cerebral aneurysms. Arch Neurol 8:272–285PubMedCrossRefGoogle Scholar
  81. 81.
    Stehbens WE (1989) Etiology of intracranial berry aneurysms. J Neurosurg 70:823–831PubMedCrossRefGoogle Scholar
  82. 82.
    Szikora I, Seifert P, Hanzely Z et al (2006) Histopathologic evaluation of aneurysms treated with Guglielmi detachable coils or matrix detachable microcoils. AJNR Am J Neuroradiol 27:283–288PubMedGoogle Scholar
  83. 83.
    Tedgui A, Lever MJ (1984) Filtration through damaged and undamaged rabbit thoracic aorta. Am J Physiol 247:H784–H791PubMedGoogle Scholar
  84. 84.
    Todor DR, Lewis I, Bruno G et al (1998) Identification of a serum gelatinase associated with the occurrence of cerebral aneurysms as pro-matrix metalloproteinase-2. Stroke 29:1580–1583PubMedCrossRefGoogle Scholar
  85. 85.
    Tulamo R, Frösen J, Junnikkala S et al (2006) Complement activation associates with saccular cerebral artery aneurysm wall degeneration and rupture. Neurosurgery 59:1069–1076PubMedGoogle Scholar
  86. 86.
    Tulamo R, Frösen J, Junnikkala S et al (2010) Complement system becomes activated by the classical pathway in intracranial aneurysm walls. Lab Invest 90:168–179PubMedCrossRefGoogle Scholar
  87. 87.
    Tulamo R, Frösen J, Paetau A et al (2010) Lack of complement inhibitors in the outer intracranial artery aneurysm wall associates with complement terminal pathway activation. Am J Pathol 177:3224–3232PubMedCrossRefGoogle Scholar
  88. 88.
    Ueda S, Masutani H, Nakamura H et al (2002) Redox control of cell death. Antioxid Redox Signal 4:405–414PubMedCrossRefGoogle Scholar
  89. 89.
    Ujiie H, Tachibana H, Hiramatsu O et al (1999) Effects of size and shape (aspect ratio) on the hemodynamics of saccular aneurysms: a possible index for surgical treatment of intracranial aneurysms. Neurosurgery 45:119–129PubMedCrossRefGoogle Scholar
  90. 90.
    Virchow VR (1847) Uber die akute Entzundung der Arterien. Virchows Arch A Pathol Anat Histopathol 1:272–378Google Scholar
  91. 91.
    Weir B, Amidei C, Kongable G (2003) The aspect ratio (dome/neck) of ruptured and unruptured aneurysms. J Neurosurg 99:447–451PubMedCrossRefGoogle Scholar
  92. 92.
    Wermer MJ, van der Schaaf IC et al (2007) Risk of rupture of unruptured intracranial aneurysms in relation to patient and aneurysm characteristics: an updated meta-analysis. Stroke 38:1404–1410PubMedCrossRefGoogle Scholar
  93. 93.
    Wiebers DO, Whisnant JP, Huston J 3rd (2003) Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 362:103–110PubMedCrossRefGoogle Scholar
  94. 94.
    Yasui N, Suzuki A, Nishimura H et al (1997) Long-term follow-up study of unruptured intracranial aneurysms. Neurosurgery 40:1155–1159PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Juhana Frösen
    • 1
    • 2
  • Riikka Tulamo
    • 2
  • Anders Paetau
    • 3
  • Elisa Laaksamo
    • 2
  • Miikka Korja
    • 1
    • 2
  • Aki Laakso
    • 1
    • 2
  • Mika Niemelä
    • 1
    • 2
  • Juha Hernesniemi
    • 1
    • 2
  1. 1.Department of NeurosurgeryHelsinki University Central HospitalHelsinkiFinland
  2. 2.Neurosurgery Research GroupBiomedicum HelsinkiHelsinkiFinland
  3. 3.Department of PathologyHelsinki University Central HospitalHelsinkiFinland

Personalised recommendations