Virchows Archiv

, Volume 474, Issue 2, pp 235–245 | Cite as

Cerebrovascular pathology in cerebral amyloid angiopathy presenting as intracerebral haemorrhage

  • Rajalakshmi Poyuran
  • Anita MahadevanEmail author
  • Arivazhagan Arimappamagan
  • B. N. Nandeesh
  • Madhu Nagappa
  • Jitender Saini
  • K. V. L. Narasinga Rao
  • Yasha T. Chickabasaviah
Original Article


Cerebral amyloid angiopathy (CAA) is the second most common cause of non-traumatic intracerebral haemorrhage (ICH) accounting for 12–15% of lobar haemorrhages in the elderly. Definitive diagnosis of CAA requires histological evaluation. We aimed to evaluate the spectrum of cerebrovascular changes in CAA-related ICH. Between 2011 and 2015, biopsy-confirmed cases of CAA were retrieved and clinical, radiological and pathological features were reviewed. The spectrum of vascular alterations was evaluated and amyloid deposition was graded in accordance with the Greenberg and Vonsattel scale. Seven cases of sporadic CAA [5 males and 2 females] were diagnosed, none of whom were suspected to have CAA pre-operatively. Six presented with large intracerebral haematoma (ICH) requiring neurosurgical intervention (age range: 56–70 years) and one had episodic headache and multiple microhaemorrhages requiring a diagnostic brain biopsy (45 years). In the presence of large ICH, vascular amyloid deposits were of moderate to severe grade (grade 4 in 4, grades 2 and 3 in 1 case each) with predominant involvement of medium (200–500 μm) to large (> 500 μm) leptomeningeal vessels. Fibrinoid necrosis was noted in four. Two were hypertensive and on antiplatelet agents. β-Amyloid plaques were detected in two, one of whom had symptomatic dementia. MRI performed in 3 of 6 cases with ICH did not reveal any microhaemorrhages. Amyloid deposits in small (50–200 μm) to medium (200–500 μm) calibre intracortical vessels produced parenchymal microhemorrhages. Histopathological examination of ICH is essential for diagnosing CAA. The vascular calibre rather than grade of amyloid deposits dictates size of the bleed. Presence of co-morbidities such as antiplatelet agents may predispose to haemorrhage.


Amyloid deposits Grade Aβ Lobar hematoma Microhemorrhage 



We would like to acknowledge Dr. Natarajan M, Neurosugeon, K G Hospital, Coimbatore, Tamil Nadu, India for referring a case for histopathological diagnosis.

Authors’ contributions

Author 1, Rajalakshmi Poyuran, -analysed the cases; performed data collection, analysis and interpretation; drafted the manuscript and reviewed the literature.

Author 2, Anita Mahadevan, conceived and designed the study, performed data interpretation and analysis and critically reviewed and finalized the manuscript.

Authors 3 and 7, Arimappamagan Arivazhagan and K V L Narasinga Rao, are neurosurgeons who operated and managed the patients and performed clinical data acquisition, analysis and review of the manuscript with intellectual inputs.

Authors 4 and 8, Nandeesh BN and Yasha T Chickabasaviah, performed diagnosis of cases, data analysis and interpretation; reviewed the manuscript and provided inputs.

Author 5, Madhu Nagappa, is a neurologist who managed the patients, provided and interpreted clinical data, performed clinicopathological analysis and reviewed the manuscript with intellectual inputs.

Author 6, Jitender Saini, is a neuroradiologist who carried out neuroimaging studies, reviewed imaging findings and analysed and interpreted the neuroimaging data and reviewed the manuscript providing critical inputs.

All the authors gave final approval for publication and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author takes full responsibility for the work as a whole, including the study design, access to data and the decision to submit and publish the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Pezzini A, Padovani A (2008) Cerebral amyloid angiopathy-related hemorrhages. Neurol Sci 29:260–263. CrossRefGoogle Scholar
  2. 2.
    Knudsen KA, Rosand J, Karluk D, Greenberg SM (2001) Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria. Neurology 56:537–539CrossRefGoogle Scholar
  3. 3.
    Greenberg SM, Vonsattel JP (1997) Diagnosis of cerebral amyloid angiopathy. Sensitivity and specificity of cortical biopsy. Stroke 28:1418–1422CrossRefGoogle Scholar
  4. 4.
    Vonsattel JP, Myers RH, Hedley-Whyte ET, Ropper AH, Bird ED, Richardson EPJ Jr (1991) Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study. Ann Neurol 30:637–649CrossRefGoogle Scholar
  5. 5.
    Oppenheim G (1909) Über “drusige Nekrosen” in der Grosshirnrinde. Neurol Centralbl 28:410–413Google Scholar
  6. 6.
    Pantelakis S (1954) A particular type of senile angiopathy of the central nervous system: congophilic angiopathy cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study, topography and frequency. Monatsschr Psychiatr Neurol 128:219–256CrossRefGoogle Scholar
  7. 7.
    Okazaki H, Reagan TJ, Campbell RJ (1979) Clinicopathologic studies of primary cerebral amyloid angiopathy. Mayo Clin Proc 54:22–31Google Scholar
  8. 8.
    Biffi A, Greenberg SM (2011) Cerebral amyloid angiopathy: a systematic review. J Clin Neurol 7:1–9. CrossRefGoogle Scholar
  9. 9.
    Mehndiratta P, Manjila S, Ostergard T, Eisele S, Cohen ML, Sila C, Selman WR (2012) Cerebral amyloid angiopathy–associated intracerebral hemorrhage: pathology and management. Neurosurg Focus 32:E7. CrossRefGoogle Scholar
  10. 10.
    Iadecola C (2003) Cerebrovascular effects of amyloid-beta peptides: mechanisms and implications for Alzheimer’s dementia. Cell Mol Neurobiol 23:681–689CrossRefGoogle Scholar
  11. 11.
    Zipfel GJ, Han H, Ford AL, Lee JM (2009) Cerebral amyloid angiopathy: progressive disruption of the neurovascular unit. Stroke 40:S16–S19. CrossRefGoogle Scholar
  12. 12.
    Jung SS, Zhang W, Van Nostrand WE (2003) Pathogenic A beta induces the expression and activation of matrix metalloproteinase-2 in human cerebrovascular smooth muscle cells. J Neurochem 85:1208–1215CrossRefGoogle Scholar
  13. 13.
    Lee JM, Yin KJ, Hsin I, Chen S, Fryer JD, Holtzman DM, Hsu CY, Xu J (2003) Matrix metalloproteinase-9 and spontaneous hemorrhage in an animal model of cerebral amyloid angiopathy. Ann Neurol 54:379–382CrossRefGoogle Scholar
  14. 14.
    Meretoja A, Strbian D, Putaala J, Curtze S, Haapaniemi E, Mustanoja S, Sairanen T, Satopää J, Silvennoinen H, Niemelä M, Kaste M, Tatlisumak T (2012) SMASH-U: a proposal for etiologic classification of intracerebral hemorrhage. Stroke 43:2592–2597. CrossRefGoogle Scholar
  15. 15.
    Yeh SJ, Tang SC, Tsai LK, Jeng JS (2014) Pathogenetical subtypes of recurrent intracerebral hemorrhage: designations by SMASH-U classification system. Stroke 45:2636–2642. CrossRefGoogle Scholar
  16. 16.
    Hirohata M, Yoshita M, Ishida C, Ikeda SI, Tamaoka A, Kuzuhara S, Shoji M, Ando Y, Tokuda T, Yamada M (2010) Clinical features of non-hypertensive lobar intracerebral hemorrhage related to cerebral amyloid angiopathy. Eur J Neurol 17:823–829. CrossRefGoogle Scholar
  17. 17.
    Mandybur TI (1986) Cerebral amyloid angiopathy: the vascular pathology and complications. J Neuropathol Exp Neurol 45:79–90CrossRefGoogle Scholar
  18. 18.
    Li XQ, Su DF, Chen HS, Fang Q (2015) Clinical neuropathological analysis of 10 cases of cerebral amyloid angiopathy-related cerebral lobar hemorrhage. J Korean Neurosurg Soc 58:30–35. CrossRefGoogle Scholar
  19. 19.
    Panicker JN, Nagaraja D, Chickabasaviah YT (2010) Cerebral amyloid angiopathy: a clinicopathological study of three cases. Ann Indian Acad Neurol 13:216–220. CrossRefGoogle Scholar
  20. 20.
    Gurol ME, Dierksen G, Betensky R, Gidicsin C, Halpin A, Becker A, Carmasin J, Ayres A, Schwab K, Viswanathan A, Salat D, Rosand J, Johnson KA, Greenberg SM (2012) Predicting sites of new hemorrhage with amyloid imaging in cerebral amyloid angiopathy. Neurology 79:320–326. CrossRefGoogle Scholar
  21. 21.
    Wagle WA, Smith TW, Weiner M (1984) Intracerebral hemorrhage caused by cerebral amyloid angiopathy: radiographic-pathologic correlation. Am J Neuroradiol 5:171–176Google Scholar
  22. 22.
    Doubal FN, Mac Lullich AM, Ferguson KJ, Dennis MS, Wardlaw JM (2010) Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease. Stroke 41:450–454. CrossRefGoogle Scholar
  23. 23.
    Charidimou A, Jaunmuktane Z, Baron J, Burnell M, Varlet P, Peeters A, Xuereb J, Jäger R, Brandner S, Werring DJ (2014) White matter perivascular spaces an MRI marker in pathology-proven cerebral amyloid angiopathy? Neurology 82:57–62. CrossRefGoogle Scholar
  24. 24.
    Linn J, Halpin A, Demaerel P, Ruhland J, Giese AD, Dichgans M, van Buchem MA, Bruckmann H, Greenberg SM (2010) Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy. Neurology 74:1346–1350. CrossRefGoogle Scholar
  25. 25.
    Walker DA, Broderick DF, Kotsenas AL, Rubino FA (2004) Routine use of gradient-echo MRI to screen for cerebral amyloid angiopathy in elderly patients. Am J Roentgenol 182:1547–1550. CrossRefGoogle Scholar
  26. 26.
    Atlas SW, Mark AS, Grossman RI, Gomori JM (1988) Intracranial hemorrhage: gradient-echo MR imaging at 1.5 T-comparison with spin-echo imaging and clinical applications. Radiology 168:803–807CrossRefGoogle Scholar
  27. 27.
    Chao CP, Kotsenas AL, Broderick DF (2006) Cerebral amyloid angiopathy: CT and MR imaging findings. RadioGraphics 26:1517–1531. CrossRefGoogle Scholar
  28. 28.
    Dierksen GA, Skehan ME, Khan MA, Jeng J, Nandigam RN, Becker JA, Kumar A, Neal KL, Betensky RA, Frosch MP, Rosand J, Johnson KA, Viswanathan A, Salat DH, Greenberg SM (2010) Spatial relation between microbleeds and amyloid deposits in amyloid angiopathy. Ann Neurol 68:545–548. CrossRefGoogle Scholar
  29. 29.
    van Etten ES, Auriel E, Haley KE, Ayres AM, Vashkevich A, Schwab KM, Rosand J, Viswanathan A, Greenberg SM, Gurol ME (2014) Incidence of symptomatic hemorrhage in patients with lobar microbleeds. Stroke 45:2280–2285. CrossRefGoogle Scholar
  30. 30.
    Greenberg SM, Eng JA, Ning M, Smith EE, Rosand J (2004) Hemorrhage burden predicts recurrent intracerebral hemorrhage after lobar hemorrhage. Stroke 35:1415–1420. CrossRefGoogle Scholar
  31. 31.
    Charidimou A, Kakar P, Fox Z, Werring DJ (2013) Cerebral microbleeds and the risk of intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 84:277–280. CrossRefGoogle Scholar
  32. 32.
    Charidimou A, Shakeshaft C, Werring DJ (2012) Cerebral microbleeds on magnetic resonance imaging and anticoagulant-associated intracerebral hemorrhage risk. Front Neurol 3:133. CrossRefGoogle Scholar
  33. 33.
    Vernooij MW, Haag MD, van der Lugt A, Hofman A, Krestin GP, Stricker BH, Breteler MM (2009) Use of antithrombotic drugs and the presence of cerebral microbleeds: the Rotterdam scan study. Arch Neurol 66:714–720. CrossRefGoogle Scholar
  34. 34.
    Vinters HV (1987) Cerebral amyloid angiopathy. A critical review. Stroke 18:311–324CrossRefGoogle Scholar
  35. 35.
    Gregoire SM, Charidimou A, Gadapa N, Dolan E, Antoun N, Peeters A, Vandermeeren Y, Laloux P, Baron JC, Jäger HR, Werring DJ (2011) Acute ischaemic brain lesions in intracerebral haemorrhage: multicentre cross-sectional magnetic resonance imaging study. Brain 134:2376–2386. CrossRefGoogle Scholar
  36. 36.
    Arima H, Tzourio C, Anderson C, Woodward M, Bousser MG, MacMahon S, Neal B, Chalmers J (2010) Effects of perindopril-based lowering of blood pressure on intracerebral hemorrhage related to amyloid angiopathy: the PROGRESS trial. Stroke 41:394–396. CrossRefGoogle Scholar
  37. 37.
    Passero S, Burgalassi L, D’Andrea P, Battistini N (1995) Recurrence of bleeding in patients with primary intracerebral hemorrhage. Stroke 26:1189–1192CrossRefGoogle Scholar
  38. 38.
    Tang YJ, Wang S, Zhu MW, Sun YL, Zhao JZ (2013) Severe pathological manifestation of cerebral amyloid angiopathy correlates with poor outcome from cerebral amyloid angiopathy related intracranial hemorrhage. Chin Med J 126:603–608Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Rajalakshmi Poyuran
    • 1
  • Anita Mahadevan
    • 1
    Email author
  • Arivazhagan Arimappamagan
    • 2
  • B. N. Nandeesh
    • 1
  • Madhu Nagappa
    • 3
  • Jitender Saini
    • 4
  • K. V. L. Narasinga Rao
    • 2
  • Yasha T. Chickabasaviah
    • 1
  1. 1.Department of NeuropathologyNational Institute of Mental Health & Neurosciences (NIMHANS)BangaloreIndia
  2. 2.Department of NeurosurgeryNational Institute of Mental Health & Neurosciences (NIMHANS)BangaloreIndia
  3. 3.Department of NeurologyNational Institute of Mental Health & Neurosciences (NIMHANS)BangaloreIndia
  4. 4.Department of Neuroimaging and Interventional RadiologyNational Institute of Mental Health & Neurosciences (NIMHANS)BangaloreIndia

Personalised recommendations