**4. Neuroimaging correlates of CAA**

**2. Pathophysiology**

42 Intracerebral Hemorrhage

**3. Clinical spectrum**

ment and dementia. [7]

with confusion and disorientation. [3]

[8]

yellow-green birefringence under polarized light. [3]

CAA is characterized by deposition of β-amyloid protein in media and adventitia of small and medium-sized cortical, subcortical, and leptomeningeal vessels, with sparing of similar-sized vessels in the deep white matter. [2] The complex structural changes in the vessel wall related to β-amyloid deposition include endothelial dysfunction, loss of smooth muscle cells, fibrinoid necrosis, vessel wall fragmentation (fragile vessel) and microaneurysm formation. All these factors predispose the patient to repeated episodes of blood vessel leakage and frank hemor‐ rhages in response to sudden increase in blood pressure or minor trauma. [3,4] CAA related inflammation (termed as cerebral amyloid angitis or cerebral amyloid inflammatory vascul‐ opathy) is typically perivascular and may be associated with frank vasculitis. β-amyloid deposition causes vessel wall thickening and subsequent luminal narrowing leading to ischemic changes. [2] The deposition may also impair the perivascular drainage, leading to dilatation of perivascular spaces (also known as Virchow Robin spaces) within the lobar region and in deep cerebral white matter. The enlarged perivascular spaces, a potential useful neuroimaging marker of CAA, can reach several millimeters in diameter and may be visible on brain imaging. [5,6] Histologically, β-amyloid deposits stained with Congo red show classic

In general, hereditary form of CAA has an earlier onset and more severe clinical manifestations than sporadic CAA. Symptomatic CAA has variable clinical presentations, which include sudden neurologic deficit (stroke) related to acute ICH, TIA-like symptoms, cognitive impair‐

The most common presentation of CAA is the development of a sudden neurological deficit secondary to an acute ICH. Specific clinical symptoms and signs depend on both the size and location of the ICH. CAA can have similar presentation as acute ICH related to other causes: headache, nausea and vomiting, loss of consciousness, focal neurological deficits and seizures.

Transient-ischemic attack (TIA) like symptoms also termed as "amyloid spells" is the next most commonly described presentation. The spells are typically brief (<30mts) and are characterized by recurrent, stereotyped episodes of 'positive' spreading sensory symptoms (paraesthesias). The spells are related to hemorrhagic components of CAA, for example cortical microbleeds (CMBs), cortical subarachnoid hemorrhage (cSAH), or cortical superficial siderosis. [4,9]

The prevalence of CAA is significantly higher in demented patients (due to Alzheimer disease) compared to non-demented patients. CAA-related dementia is slowly progressive, similar to that seen in patients with Alzheimer disease. [10] CAA is also the direct cause of cognitive impairment that progresses rapidly over the course of a few weeks. These patients may present

**The Boston criteria** (table 1) was first proposed in 1990 in order to standardize the diagnosis of cerebral amyloid angiopathy. They comprise of combined clinical, imaging and pathological parameters. [11]


**Table 1.** Boston criteria for diagnosis of CAA-related hemorrhage

Recognition of the imaging findings of CAA is important for correct diagnosis. The important imaging correlates of CAA include: (i) large intracranial hemorrhages (ICHs), (ii) cerebral microbleeds (CMBs), (iii) convexity subarachnoid hemorrhages (cSAH), (iv) cortical superfi‐ cial siderosis, (v) white matter changes (leukoaraiosis), and (vi) prominent VRSs.

The majority of ICHs (>75%) in elderly are spontaneous due to rupture of small arteries affected by either of the two processes; the hypertensive arteriopathy or CAA. Distribution of ICH reflects the underlying microangiopathy. Hypertensive arteriopathy is characterized by lipohyalinosis and fibrinoid necrosis of lenticulostriate perforators located in deep gray nuclei (i. e. basal ganglia, thalami) and infratentorial location (i. e. pons). In contrast, CAA related ICH is preferentially lobar (any lobe may be involved); less commonly involves the cerebellum and rarely the deep nuclei or the brainstem. [12] CAA-related ICH represents 2% of all ICH and is an important cause of hemorrhage in normotensive elderly patients without trauma. Nonenhanced CT helps to exclude the presence or absence of an acute ICH and provides information regarding the location, size, shape and extension of ICH (Figure 1). MR imaging is most sensitive for detection of chronic hemorrhages in suspected cases of CAA. After ICH, hemosiderin remains stored within the macrophages, leads to focal dephasing of the MR signal, and causes hemosiderin-containing areas to appear dark on T2-weighted spin-echo sequences. This effect may be further enhanced by the use of imaging techniques with high sensitivity for differences in magnetic susceptibility, such as the T2\*-weighted gradient-echo (GRE) sequence (Figure 2). The susceptibility-weighted imaging (SWI) has been found to be more sensitive than conventional GRE techniques for the detection of blood products. [13,14,15]

**Figure 1.** Plain axial CT image of a 66-year-old normotensive male reveals a large, right parietal lobe, hyperdense, sub‐ acute hemorrhage (arrow) causing mass effect in form of effacement of adjacent sulci and compression of posterior part of the body of ipsilateral lateral ventricle. Diffuse periventricular white matter hypodensities (leukoaraiosis) is also noted.

The hemorrhage is typically lobar and cortical-subcortical in distribution; it generally spares the deep white matter, basal ganglia and the brainstem. Symptomatic ICH is large (>5mm), while microhemorrhages (<5mm) are often clinically silent. CAA-related macrohemorrhages typically exhibit irregular borders (Figure 1) and may be associated with subarachnoid hemorrhage, subdural hemorrhage, or, less commonly, intraventricular hemorrhage. CMBs are small, well demarcated; rounded lesions not detected on conventional MRI (Figure 2). The presence of chronic cortical-subcortical microhemorrhages in association with large ICH increases the probability of CAA (Figure 3). Multiplicity and recurrence of ICH further favors CAA. [16,17]

**Figure 3.** T2\*-weighted gradient-echo MR image of same patient as in figure 1, demonstrates a large right parietal hematoma in association with multiple chronic cortical-subcortical microhemorrhages (arrows) and periventricular

**Figure 2.** T2\*-weighted gradient-echo MR image of a 62-year-old male patient shows diffuse and small multifocal he‐ mosiderin deposits (chronic microhemorrhages) in corticosubcortical location of both the cerebral hemispheres, seen

Cerebral Amyloid Angiopathy http://dx.doi.org/10.5772/58461 45

white matter abnormality (asterisk), thus increasing the probability of CAA.

as signal void areas (blooming) (arrows).

Nonenhanced CT helps to exclude the presence or absence of an acute ICH and provides information regarding the location, size, shape and extension of ICH (Figure 1). MR imaging is most sensitive for detection of chronic hemorrhages in suspected cases of CAA. After ICH, hemosiderin remains stored within the macrophages, leads to focal dephasing of the MR signal, and causes hemosiderin-containing areas to appear dark on T2-weighted spin-echo sequences. This effect may be further enhanced by the use of imaging techniques with high sensitivity for differences in magnetic susceptibility, such as the T2\*-weighted gradient-echo (GRE) sequence (Figure 2). The susceptibility-weighted imaging (SWI) has been found to be more sensitive than conventional GRE techniques for the detection of blood products.

**Figure 1.** Plain axial CT image of a 66-year-old normotensive male reveals a large, right parietal lobe, hyperdense, sub‐ acute hemorrhage (arrow) causing mass effect in form of effacement of adjacent sulci and compression of posterior part of the body of ipsilateral lateral ventricle. Diffuse periventricular white matter hypodensities (leukoaraiosis) is also

The hemorrhage is typically lobar and cortical-subcortical in distribution; it generally spares the deep white matter, basal ganglia and the brainstem. Symptomatic ICH is large (>5mm), while microhemorrhages (<5mm) are often clinically silent. CAA-related macrohemorrhages typically exhibit irregular borders (Figure 1) and may be associated with subarachnoid hemorrhage, subdural hemorrhage, or, less commonly, intraventricular hemorrhage. CMBs are small, well demarcated; rounded lesions not detected on conventional MRI (Figure 2). The presence of chronic cortical-subcortical microhemorrhages in association with large ICH increases the probability of CAA (Figure 3). Multiplicity and recurrence of ICH further favors

[13,14,15]

44 Intracerebral Hemorrhage

noted.

CAA. [16,17]

**Figure 2.** T2\*-weighted gradient-echo MR image of a 62-year-old male patient shows diffuse and small multifocal he‐ mosiderin deposits (chronic microhemorrhages) in corticosubcortical location of both the cerebral hemispheres, seen as signal void areas (blooming) (arrows).

**Figure 3.** T2\*-weighted gradient-echo MR image of same patient as in figure 1, demonstrates a large right parietal hematoma in association with multiple chronic cortical-subcortical microhemorrhages (arrows) and periventricular white matter abnormality (asterisk), thus increasing the probability of CAA.

Chronic subarachnoid hemorrhage (cSAH) and superficial siderosis are quite characteristic of CAA. cSAH often results from lobar ICH extending to the cortical surface (Figure 4). Cortical superficial siderosis describes hemosiderin deposition in the superficial layers of the cerebral cortex and may follow repeated episodes of bleeding in the subarachnoid space. On T2\* weighted GRE sequence, cortical superficial siderosis shows a characteristic gyriform pattern of hypointense signal. [18]

**Figure 5.** Axial MRI (FLAIR sequence) of the same patient as in figure 2, demonstrates bilateral symmetrical, confluent, supratentorial periventricular white matter hyperintensity with involvement of posterior subcortical U fibers (thick ar‐ rows). Also note dilated perivascular spaces (Virchow Robin spaces) in deep cerebral white matter (thin arrow).

Cerebral Amyloid Angiopathy http://dx.doi.org/10.5772/58461 47

Currently, there is no treatment to halt or reverse β-amyloid deposition. Thus, attention is directed instead to the prevention of adverse outcomes associated with CAA, such as recurrent hemorrhages or progressive dementia. In this context, MRI may help in selecting patients for different types of secondary prevention of stroke. MR evidence of higher number of chronic microbleeds on baseline GRE MR images are predictive of a greater risk of recurrent hemor‐ rhage and future cognitive impairment. A routine use of GRE MRI sequence is suggested to detect microbleeds in older people to avoid potentially dangerous anticoagulant or antiplatelet

The role of neurosurgery in ICH remains to be defined clearly. However, hematoma evacuation appears relatively safe in patients <75 years of age without intraventricular extension. [23] For future treatment of CAA, it is important to identify patients early in the course of disease before ICH or dementia occurs, to allow the use of disease modifying therapies. [24] Tramiprosate has been found to be a safe treatment option for patients with suspected CAA. Tramiprosate is an ionic compound that binds with soluble β-amyloid, interferes with the amyloid cascade

**5. Management prospect and prognosis**

and delays or inhibits the progression of CAA. [25]

therapy. [22]

**Figure 4.** T2\*-weighted gradient-echo MR image of same patient as in figure 1, shows two linear areas of signal void (thin arrows) in the vicinity of large primary lobar hemorrhage (thick arrow) suggest chronic subarachnoid hemor‐ rhage and cortical superficial hemosiderosis.

MRI is also sensitive for identifying CAA-related inflammation and ischemic changes and assessment of disease progression. [19] Leukoaraiosis, a radiological term which describes imaging changes in deep cerebral white matter, is a nonspecific finding seen in patients with CAA and can be due to demyelination, infarction or edema. On imaging, leukoaraiosis appears as patchy or confluent, CT hypodense or T2/FLAIR (fluid attenuated inversion recovery) hyperintense white matter abnormality with or without sparing of subcortical U fibers (Figure 5). Leukoaraiosis with sparing of U fibers is secondary to ischemic white matter damage and is seen in association with long standing dementia; whereas, white matter changes that extend to involve the U fibers are common in patients with subacute cognitive decline and are associated with mass effect due to inflammatory edema. [20,21] White matter changes in CAA increases over time and is an important contributor to overall disease burden. The CAA should be considered in the broad differential diagnosis of leukoencephalopathy especially if associated with progressive dementia or cognitive impairment. [13]

**Figure 5.** Axial MRI (FLAIR sequence) of the same patient as in figure 2, demonstrates bilateral symmetrical, confluent, supratentorial periventricular white matter hyperintensity with involvement of posterior subcortical U fibers (thick ar‐ rows). Also note dilated perivascular spaces (Virchow Robin spaces) in deep cerebral white matter (thin arrow).
