cerebral_amyloid_angiopathy-related_hemorrhage

Cerebral amyloid angiopathy-related hemorrhage

Amyloid angiopathy-associated intracerebral hemorrhage (ICH) comprises 12%-15% of lobar hemorrhage in the elderly. This growing population has an increasing incidence of thrombolysis-related hemorrhages, causing the management of hemorrhages associated with cerebral amyloid angiopathy (CAA) to take center stage. A concise reference assimilating the pathology and management of this clinical entity does not exist. Amyloid angiopathy-associated hemorrhages are most often solitary, but the natural history often progresses to include multifocal and recurrent hemorrhages. Compared with other causes of ICH, patients with CAA-associated hemorrhages have a lower mortality rate but an increased risk of recurrence. Unlike hypertensive arteriolar hemorrhages that occur in penetrating subcortical vessels, CAA-associated hemorrhages are superficial in location due to the preferential involvement of vessels in the cerebral cortex and meninges. This feature makes CAA-associated hemorrhages easier to access surgically. In this paper, the authors discuss 3 postulates regarding the pathogenesis of amyloid hemorrhages, as well as the established clinicopathological classification of amyloid angiopathy and CAA-associated ICH. Common inheritance patterns of familial CAA with hemorrhagic strokes are discussed along with the role of genetic screening in relatives of patients with CAA. The radiological characteristics of CAA are described with specific attention to CAA-associated microhemorrhages. The detection of these microhemorrhages may have important clinical implications on the administration of anticoagulation and antiplatelet therapy in patients with probable CAA. Poor patient outcome in CAA-associated ICH is associated with dementia, increasing age, hematoma volume and location, initial Glasgow Coma Scale score, and intraventricular extension 1).


Cortical subarachnoid hemorrhage.

Patients with cerebral amyloid angiopathy (CAA) are also at increased risk of ICH following administration of antiplatelet drugs or anticoagulants.


Primary lobar hemorrhages (usually due to cerebral amyloid angiopathy) are typically seen in elderly. Younger patients may also develop lobar hemorrhages, but in such cases, they usually have an underlying lesion (e.g. cerebral arteriovenous malformation).

Patients with lobar hemorrhage or cerebral amyloid angiopathy remain at higher risk for anticoagulant-related Intracerebral hemorrhage (ICH) recurrence than thromboembolic events and, therefore would be best managed without anticoagulants.

Patients with deep hemispheric ICH and a baseline risk of ischemic stroke >6.5% per year, that corresponds to CHADS2≥ 4 or CHA2DS2-VASc ≥ 5, may receive net benefit from restarting anticoagulation. To date, a reasonable recommendation regarding time to resumption of anticoagulation therapy would be after 10 weeks. Available data regarding the role of magnetic resonance imaging in assessing the risks of both ICH and warfarin-related ICH do not support the use of this test for excluding anticoagulation in patients with atrial fibrillation 2).

Neuropathologically defined CAA cohort suggests that cortical superficial siderosis (CSS) and APOE ε2 are related to the hemorrhagic expression of the disease; APOE ε4 is enriched in nonhemorrhagic CAA. The study emphasizes the concept of different CAA phenotypes, suggesting divergent pathophysiologic mechanisms 3).


The Boston criteria for CAA-related hemorrhage can be used to attribute an ICH with increasing certainty to CAA by using clinical data, imaging signs, and—if available—histopathologic findings. The definite diagnosis requires a full postmortem examination 4).


Cerebral amyloid angiopathy is a common form of small-vessel disease and an important risk factor for cognitive impairment. The mechanisms linking small-vessel disease to cognitive impairment is associated with functionally relevant brain network impairments, in particular affecting posterior white matter connections 5).


In ischemic stroke or patients with TIA less than five cerebral microbleeds (CMBs) should not affect antithrombotic decisions, although with more than five CMBs the risks of future ICH and ischaemic stroke are finely balanced, and antithrombotics might cause net harm. In lobar ICH populations, a high burden of strictly lobar CMBs is associated with cerebral amyloid angiopathy (CAA) and high ICH risk; antithrombotics should be avoided unless there is a compelling indication 6).

Nearly 50% of cerebral amyloid angiopathy-related hemorrhage patients achieved favorable outcomes at long-term follow-up. GCS, recurrence of intracerebral hemorrhage, white matter lesions (WML) grade, and cerebral atrophy were identified as independent prognostic factors of long-term outcome 7).


1)
Mehndiratta P, Manjila S, Ostergard T, Eisele S, Cohen ML, Sila C, Selman WR. Cerebral amyloid angiopathy-associated intracerebral hemorrhage: pathology and management. Neurosurg Focus. 2012 Apr;32(4):E7. doi: 10.3171/2012.1.FOCUS11370. PMID: 22463117.
2)
Paciaroni M, Agnelli G. Should oral anticoagulants be restarted after warfarin-associated cerebral haemorrhage in patients with atrial fibrillation? Thromb Haemost. 2014 Jan 8;111(1):14-8. doi: 10.1160/TH13-08-0667. Epub 2013 Nov 21. PubMed PMID: 24258528.
3)
Charidimou A, Martinez-Ramirez S, Shoamanesh A, Oliveira-Filho J, Frosch M, Vashkevich A, Ayres A, Rosand J, Gurol ME, Greenberg SM, Viswanathan A. Cerebral amyloid angiopathy with and without hemorrhage: Evidence for different disease phenotypes. Neurology. 2015 Feb 25. pii: 10.1212/WNL.0000000000001398. [Epub ahead of print] PubMed PMID: 25716356.
4)
Knudsen KA, Rosand J, Karluk D, Greenberg SM. Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria. Neurology 2001;56:537–539.
5)
Reijmer YD, Fotiadis P, Martinez-Ramirez S, Salat DH, Schultz A, Shoamanesh A, Ayres AM, Vashkevich A, Rosas D, Schwab K, Leemans A, Biessels GJ, Rosand J, Johnson KA, Viswanathan A, Gurol ME, Greenberg SM. Structural network alterations and neurological dysfunction in cerebral amyloid angiopathy. Brain. 2015 Jan;138(Pt 1):179-88. doi: 10.1093/brain/awu316. Epub 2014 Nov 2. PubMed PMID: 25367025; PubMed Central PMCID: PMC4285191.
6)
Wilson D, Werring DJ. Antithrombotic therapy in patients with cerebral microbleeds. Curr Opin Neurol. 2016 Nov 24. [Epub ahead of print] PubMed PMID: 27898582.
7)
Che R, Zhang M, Sun H, Ma J, Hu W, Liu X, Ji X. Long-term outcome of cerebral amyloid angiopathy-related hemorrhage. CNS Neurosci Ther. 2022 Aug 16. doi: 10.1111/cns.13922. Epub ahead of print. PMID: 35975394.
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