CEREBRAL HEMORRHAGE

Cerebral amyloid angiopathy (CAA)

Created 13/04/2021, last revision 06/11/2023

a heterogeneous group of sporadic or familial disorders characterized by deposition of amyloid beta-peptide (Aβ) in the walls of small to medium-sized cerebral and leptomeningeal vessels in the absence of systemic amyloidosis
- sporadic form – affects mainly the elderly population
- rare familial forms (Icelandic, Arctic, or Dutch type) – occur at younger ages
CAA is responsible for ~2-10% of primary intracranial hemorrhages (30-70% of lobar hematomas in elderly patients) [Chao, 2006]
CAA may also present with transient neurologic symptoms or encephalopathy

The APP (Amyloid Precursor Protein) gene

a transmembrane protein whose exact function is still under exploration; it is thought to be involved in neuronal development, synapse formation, and repair mechanisms within the nervous system
mutations can lead to an altered production or structure of amyloid-beta, which may result in familial forms of Alzheimer’s Disease or CAA (e.g., the Dutch, Italian, Arctic, Iowa, Flemish, and Piedmont types)
these mutations often result in increased production or altered clearance of Aβ peptides, which can accumulate in cerebral vessels

CST3 gene

the CST3 gene encodes the protein cystatin C, a potent inhibitor of lysosomal proteases known as cathepsins
cystatin C is critical for preventing the excessive breakdown of proteins by cathepsins in the body’s cells
mutations in the CST3 gene are associated with Hereditary Cystatin C Amyloid Angiopathy (HCCAA), a type of familial CAA prevalent in Iceland
genetic testing can help identify individuals at risk for HCCAA
the CST3 gene and cystatin C have been studied for associations with other conditions such as Alzheimer’s disease, kidney disease, and cardiovascular risk

ITM2B gene

the ITM2B gene encodes the Integral Membrane Protein 2B (aka BRI2)
- BRI2 is believed to play a role in protein processing and trafficking
mutations are associated with familial forms of CAA, specifically the British and Danish types
these mutations lead to abnormal processing of the BRI2 protein, resulting in the accumulation of amyloidogenic peptides in cerebral vessels

Pathology

amyloid deposition in small to medium-sized cerebral arteries without systemic amyloidosis
- type 1 CAA- amyloid deposits in cortical capillaries, leptomeningeal and cortical arteries, and arterioles
- type 2 CAA – deposits are present in leptomeningeal and cortical arteries but not in capillaries
there is some association with typical Alzheimer’s changes, such as neuritic plaques and neurofibrillary tangles
the reason for the increased deposition of Aβ in sporadic CAA is still unclear (a combination of increased production of the peptide with abnormal clearance has been proposed)
increased production is the dominant cause in familial forms
apolipoprotein E (APOE) ε2 and ε4 are associated with an increased risk of CAA

Transient Focal Neurological Episodes (TFNE), also called “amyloid spells“
recurrent lobar intracerebral hemorrhage (ICH)
convexal nontraumatic subarachnoid hemorrhage
hemocephalus
arteriolopathy with leukoaraiosis and encephalopathy
development of vascular dementia in advanced stages of the disease

Transient focal neurological episodes (TFNE), also called “amyloid spells”)
- positive symptoms – “aura-like” spreading paresis, visual phenomena (monocular blurred vision, flashes, teichopsia), limb twitching
- negative symptoms – transient focal symptoms – paresis, speech, and visual disturbances
positive symptoms predominate
typically, multiple stereotyped episodes occur, each lasting 10-30 minutes
approx. 14% of CAA patients exhibit such symptoms [Charidimou, 2012]
often caused by convexal SAH
- FLAIR, DWI/ADC, and GRE/SWI are optimal for diagnostic workup
- frequently, convexial SAH is seen along with microbleeds or parenchymal hematoma, but also with recent lesions on DWI – etiology is heterogeneous
spells may be confused with TIA (antithrombotic drugs further increase the risk of ICH) or stroke (high risk of ICH during thrombolysis)
TFNE often precede subsequent ICH (37.5%/2 months)!! [Charidimou, 2012]

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no causal treatment
monitor and treat arterial hypertension
treat acute hematoma according to standard protocols → management of intracerebral hemorrhage
antiplatelet and anticoagulant therapy increases the risk of bleeding ⇒ assess individual risk-benefit ratio in each patient (Biffi, 2010]

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IVT is a reasonable treatment option in patients with CMBs < 10 (AHA/ASA 2019 IIa/B-NR)
with CMBs >10, IVT is associated with a higher risk of ICH; the expected benefit of treatment must outweigh the risk (AHA/ASA 2019 IIb/B-NR)
- consider IVT in a patient with a severe deficit, taking into account premorbid health status and the presence of other risk factors