DOI: 10.1148/rg.265055090
RadioGraphics 2006;26:1517-1531
© RSNA, 2006
Cerebral Amyloid Angiopathy: CT and MR Imaging Findings1
Christine P. Chao, MD,
Amy L. Kotsenas, MD and
Daniel F. Broderick, MD
1 From the Department of Radiology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224. Recipient of a Certificate of Merit award for an education exhibit at the 2004 RSNA Annual Meeting. Received April 17, 2005; revision requested July 12 and received September 8; accepted September 14. All authors have no financial relationships to disclose.
Address correspondence to A.L.K. (e-mail: kotsenas.amy{at}mayo.edu).
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Abstract
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Cerebral amyloid angiopathy (CAA) is an important but underrecognized cause of cerebrovascular disorders that predominantly affect elderly patients. CAA results from deposition of ß-amyloid protein in cortical, subcortical, and leptomeningeal vessels. This deposition is responsible for the wide spectrum of clinical symptoms and neuroimaging findings. Many cases of CAA are asymptomatic. However, when cases are symptomatic, patients can present with transient neurologic events, progressive cognitive decline, or potentially devastating intracranial hemorrhage. Computed tomography is the imaging study of choice for evaluation of suspected acute cortical hemorrhage, which may be accompanied by subarachnoid, subdural, or intraventricular hemorrhage. Magnetic resonance imaging is best suited for identification of small or chronic cortical hemorrhages and ischemic sequelae of this disease, exclusion of other causes of acute cortical-subcortical hemorrhage, and assessment of disease progression. Accurate recognition of imaging findings is important in guiding clinical decision making in patients with CAA.
© RSNA, 2006
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Introduction
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Cerebral amyloid angiopathy (CAA) is an important cause of spontaneous cortical-subcortical intracranial hemorrhage (ICH) in the normotensive elderly.
CAA is a cerebrovascular disorder characterized by the deposition of ß-amyloid protein in the media and adventitia of small and medium-sized vessels of the cerebral cortex, subcortex, and leptomeninges. Both sporadic and hereditary forms may occur. Hereditary syndromes of CAA are rare and generally demonstrate autosomal dominant transmission. Hereditary forms of CAA display a broader range of clinical manifestations than the sporadic form and have been seen at a younger age, as early as the third decade in some variants (1). In contrast, the sporadic form is more common in the elderly and increases in both prevalence and severity with increasing age. The focus of this article is the more common sporadic, age-related form of CAA.
Although found at autopsy in only 33% of 60–70 year olds, the prevalence of age-related CAA increases to 75% of those older than 90 years (2). Despite its high prevalence, CAA remains an underrecognized cause of cerebrovascular disease, clinically as well as at imaging, in part because many patients are asymptomatic. When symptomatic, typical presentations include acute ICH, symptoms resembling a transient ischemic attack (TIA), or dementia. However, these symptoms are not specific for CAA and are often not readily associated with CAA.
CAA manifests radiologically as part or all of a constellation of findings including acute or chronic ICHs in a distinctive cortical-subcortical distribution, leukoencephalopathy, and atrophy.
Early recognition of such imaging findings is important; not only is the radiologist sometimes the first to raise the possibility of CAA, but the diagnosis of CAA most often requires a combination of clinical assessment and radiologic evaluation (3). With continued aging of the population, CAA will become even more prevalent, making correct characterization of imaging findings important.
In this article, we describe the histopathologic and clinical features of sporadic CAA, discuss diagnostic considerations, present the imaging features, and review management and prognosis and the differential diagnosis.
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Histopathologic Features
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CAA is characterized by the deposition of ß-amyloid protein in the media and adventitia of small and medium-sized vessels of the cerebral cortex, subcortex, and leptomeninges, with sparing of similarly sized vessels in the deep white matter (1). CAA is not associated with the presence of systemic amyloidosis (4). The structural changes in the vascular wall related to ß-amyloid deposition are associated with fibrinoid necrosis, focal vessel wall fragmentation, and microaneurysms, which all predispose the patient to repeated episodes of blood vessel leakage or frank hemorrhage. Furthermore, at sites of fibrinoid necrosis, there may be luminal narrowing, which can lead to ischemic change (4). Histologically, ß-amyloid deposits stained with Congo red show classic yellow-green birefringence under polarized light (Fig 1).
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Figure 1a. Histologic appearance of ß-amyloid deposition in cerebral cortical vessels. (a) Photomicrograph (original magnification, x100; Congo red stain) shows highlighted ß-amyloid deposits along the vessel walls. (b) Photomicrograph (original magnification, x100; Congo red stain) obtained with polarized light shows the classic yellow-green birefringence of the ß-amyloid deposits.
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Figure 1b. Histologic appearance of ß-amyloid deposition in cerebral cortical vessels. (a) Photomicrograph (original magnification, x100; Congo red stain) shows highlighted ß-amyloid deposits along the vessel walls. (b) Photomicrograph (original magnification, x100; Congo red stain) obtained with polarized light shows the classic yellow-green birefringence of the ß-amyloid deposits.
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Clinical Features
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When CAA is symptomatic, there are several clinical presentations, which include sudden neurologic deficit (stroke) related to acute ICH, symptoms resembling a TIA, or dementia.
The most common presentation of CAA is the development of a sudden neurologic deficit secondary to an acute ICH (5). Specific clinical symptoms and signs depend on both the size and location of the ICH. ICH related to CAA can have a similar presentation as acute ICH related to other causes: headache, nausea and vomiting, loss of consciousness, focal neurologic deficits, and seizures.
CAA patients may also present with symptoms resembling a TIA. Greenberg et al (6,7) noted that the TIA-like symptoms associated with CAA may be distinguished from a true TIA by the smooth spread of symptoms from one body part to another and may in fact be secondary to seizures. Distinction between these TIA-like symptoms and true TIAs may be difficult but is important, as the treatment may be different.
Dementia in CAA may be seen prior to symptomatic ICH in 25%–40% of patients. CAA-related dementia may be slowly progressive, similar to that seen in patients with Alzheimer disease dementia, with which CAA is frequently associated. Forty percent of CAA patients with dementia show changes of Alzheimer disease at autopsy. Conversely, up to 90% of patients with Alzheimer disease have changes of CAA at autopsy (1). However, dementia may be present in patients with CAA in the absence of pathologic changes of Alzheimer disease and may in those cases be related to small vessel ischemic changes (1,5). Alternatively, CAA has been seen in patients with subacute cognitive decline that progresses rapidly over the course of a few weeks. These patients may present with confusion and disorientation, without the focal neurologic deficits that may be seen in patients with a cerebral infarct or CAA-related acute ICH (8–11).
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Diagnostic Considerations: The Boston Criteria
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The clinical differentiation of CAA-related versus non–CAA-related symptomatology may be very difficult and unreliable, as there is significant overlap in diseases that result in acute neurologic deficits, TIA-like symptoms, and dementia.
The Boston criteria were developed in the mid-1990s as a tool to both improve and standardize the diagnosis of CAA (7,12). The criteria specify four diagnostic categories: definite CAA, probable CAA with supporting pathologic evidence, probable CAA, and possible CAA, depending on a combination of clinical, imaging, and histologic data.
A "definite" diagnosis of CAA is made with a full postmortem examination providing confirmation of lobar, cortical, or corticosubcortical ICH and severe CAA. Rarely, a biopsy may be performed at the time of hematoma evacuation or to exclude other causes of ICH. This pathologic tissue may reveal CAA, which with the appropriate clinical data, leads to a diagnosis of CAA as "probable with supporting pathologic evidence." CAA is considered "probable" if there is an appropriate clinical history as well as imaging findings of multiple cortical-subcortical hematomas, which may be of varying ages and sizes, in a patient 55 years old or older, with no other clinical or radiologic cause of hemorrhage. Finally, clinical data suggesting CAA and the imaging finding of a single cortical-subcortical hematoma in a patient older than 55 years, without other cause of hemorrhage, leads to a "possible" diagnosis of CAA (13) (Table).
As histologic analysis is often not practical, recognition of the imaging findings of CAA is important for correct diagnosis and proper treatment of patients. Knudsen et al (3) studied 39 cases of cortical-subcortical ICH to validate the Boston Criteria. Clinical and magnetic resonance (MR) imaging evidence of CAA was compared with results from autopsy, biopsy, or surgical evacuation of hematomas. In those patients diagnosed with "probable" CAA by means of the Boston Criteria, 13 of 13 patients (100%) had a pathologic diagnosis of CAA. A diagnosis of "possible" CAA was confirmed in 16 of 26 patients (62%) with pathologic specimens.
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Imaging of CAA
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Imaging Evaluation
The clinical presentation of a patient dictates the imaging work-up. A patient presenting with an acute neurologic deficit or TIA-like symptoms should undergo nonenhanced computed tomography (CT) of the head. CT allows rapid establishment of the presence or absence of an ICH and exclusion of the main clinical differential diagnostic consideration of an acute cerebral infarction. Nonenhanced head CT is the preferred imaging modality for initial work-up as it provides crucial information regarding the characteristics of the ICH, including size, location, shape, and extension to the extraaxial spaces (Fig 2).
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Figure 2. Determination of ICH location in a 74-year-old man with acute onset of expressive aphasia, confusion, and a right-sided facial droop. Axial nonen-hanced CT scan shows a left-sided frontal cortical ICH, a finding most consistent with CAA-related ICH. Pathologic tissue obtained at hematoma evacuation was positive for CAA. The location of an ICH is helpful in determining the cause of the ICH in a patient with a sudden neurologic deficit.
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If an ICH is present in a cortical-subcortical location suspicious for CAA, the patient should undergo additional evaluation with MR imaging including a gradient-echo (GRE) sequence. GRE is currently the most sensitive MR imaging sequence for detection of the chronic cortical-subcortical microhemorrhage. Local magnetic field inhomogeneity related to the presence of hemosiderin causes a marked loss of signal at T2*-weighted GRE imaging (Fig 3). These chronic microhemorrhages can be associated with acute CAA-related ICH, and detection of these chronic microhemorrhages with GRE imaging increases the probability for CAA.
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Figure 3a. Sensitivity of GRE imaging for hemosiderin in an 80-year-old man with dementia that has progressed over the past 4 years. (a) Axial GRE MR image shows multiple foci of signal loss in cortical-subcortical locations. In a patient with a diagnosis of probable CAA, these foci are consistent with chronic microhemorrhages. (b) Axial T2-weighted fast spin-echo MR image does not show the foci of chronic microhemorrhage.
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Figure 3b. Sensitivity of GRE imaging for hemosiderin in an 80-year-old man with dementia that has progressed over the past 4 years. (a) Axial GRE MR image shows multiple foci of signal loss in cortical-subcortical locations. In a patient with a diagnosis of probable CAA, these foci are consistent with chronic microhemorrhages. (b) Axial T2-weighted fast spin-echo MR image does not show the foci of chronic microhemorrhage.
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A patient presenting with dementia is usually evaluated initially with brain MR imaging, as the clinical presentation is often nonspecific and the causes of dementia are numerous. It is critical to maintain a high index of suspicion for CAA, especially in the elderly, and to ensure a thorough evaluation by including a GRE sequence in all patients who are 70 years old or older (14).
In general, angiography does not play a role in the evaluation of CAA.
Intracranial Hemorrhage
Often the acute presenting finding in CAA-related cerebrovascular disease, CAA-related ICH represents only 2% of all ICH but is an important cause of hemorrhage in normotensive elderly patients without trauma (1), representing 38%–74% of ICH cases in the elderly (3). Symptomatic ICH is commonly large (> 5 mm), in contrast to microhemorrhages (
5 mm), which are often clinically silent. Regardless of the size, CAA-related ICH exhibits a distinctive cortical-subcortical distribution that generally spares the deep white matter, basal ganglia, and brainstem (Fig 4a). This cortical-subcortical distribution of ICH in CAA correlates with the anatomic distribution of ß-amyloid–containing vessels (15–17). Rarely, the cerebellum is involved (18). CAA-related ICH can involve any lobe of the cerebral hemispheres (1,16,19). Other neuroimaging findings suspicious for CAA-related ICH include multiplicity (Fig 4b) and recurrence of ICH (Fig 4c).
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Figure 4a. Recurrent CAA-related ICH in a 65-year-old woman with progressive aphasia, right visual field deficits, and headache. (a) Axial nonenhanced scan from the initial CT study shows a discrete, ovoid, left-sided occipital ICH. (b) Axial GRE MR image obtained the same day shows numerous cortical-subcortical microhemorrhages, a finding most compatible with a diagnosis of probable CAA. One month later, the patient returned to the emergency department with an increasing level of confusion. (c) Axial nonenhanced CT scan obtained at that time shows a larger, more devastating, left-sided parieto-occipital hemorrhage. Owing to the presence of multiple cortical-subcortical microhemorrhages, which are highly suggestive of CAA, the larger ICH was thought to represent recurrent hemorrhage rather than a hemorrhagic infarction. The patient was not a surgical candidate and was discharged to a hospice 1 week later, where she died after a few days.
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Figure 4b. Recurrent CAA-related ICH in a 65-year-old woman with progressive aphasia, right visual field deficits, and headache. (a) Axial nonenhanced scan from the initial CT study shows a discrete, ovoid, left-sided occipital ICH. (b) Axial GRE MR image obtained the same day shows numerous cortical-subcortical microhemorrhages, a finding most compatible with a diagnosis of probable CAA. One month later, the patient returned to the emergency department with an increasing level of confusion. (c) Axial nonenhanced CT scan obtained at that time shows a larger, more devastating, left-sided parieto-occipital hemorrhage. Owing to the presence of multiple cortical-subcortical microhemorrhages, which are highly suggestive of CAA, the larger ICH was thought to represent recurrent hemorrhage rather than a hemorrhagic infarction. The patient was not a surgical candidate and was discharged to a hospice 1 week later, where she died after a few days.
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Figure 4c. Recurrent CAA-related ICH in a 65-year-old woman with progressive aphasia, right visual field deficits, and headache. (a) Axial nonenhanced scan from the initial CT study shows a discrete, ovoid, left-sided occipital ICH. (b) Axial GRE MR image obtained the same day shows numerous cortical-subcortical microhemorrhages, a finding most compatible with a diagnosis of probable CAA. One month later, the patient returned to the emergency department with an increasing level of confusion. (c) Axial nonenhanced CT scan obtained at that time shows a larger, more devastating, left-sided parieto-occipital hemorrhage. Owing to the presence of multiple cortical-subcortical microhemorrhages, which are highly suggestive of CAA, the larger ICH was thought to represent recurrent hemorrhage rather than a hemorrhagic infarction. The patient was not a surgical candidate and was discharged to a hospice 1 week later, where she died after a few days.
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Macrohemorrhages.—
Large intracerebral hemorrhage (> 5 mm in size) is most often acutely symptomatic and may manifest as headaches associated with emesis, focal neurologic deficits, seizures, coma, or death. Nonenhanced CT is the imaging study of choice in the initial evaluation of patients with suspected acute ICH, allowing rapid yet precise demonstration of location, size, and any other associated hemorrhage.
CAA-related macrohemorrhages typically exhibit irregular borders (15) and may be associated with subarachnoid hemorrhage (Fig 5), subdural hemorrhage (Fig 6), or, less commonly, intraventricular hemorrhage (Fig 7) (15–17). Subarachnoid and subdural hemorrhage may be due to direct extension of the cortical-subcortical hemorrhage into the subarachnoid or subdural space (1,20) or to primary subarachnoid or subdural hemorrhage resulting from disruption of the leptomeningeal vessels by ß-amyloid (21). Intraventricular extension of cortical-subcortical CAA-related macrohemorrhage may also be seen, depending on its size and location (1).
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Figure 5. CAA-related macrohemorrhage with associated subarachnoid hemorrhage in an 81-year-old man with acute dysphasia and agitation. Axial nonenhanced CT scan shows an irregular, 4 x 5-cm, left-sided frontoparietal cortical ICH. The high attenuation in adjacent sulci (arrowheads) is consistent with subarachnoid hemorrhage. The patient had a diagnosis of probable CAA on the basis of a history of two spontaneous right-sided frontal ICHs.
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Figure 6. CAA-related macrohemorrhage with associated subdural hemorrhage in a 77-year-old man with severe headache and difficulty walking. Axial nonenhanced CT scan shows a large right-sided posterior parietal ICH with irregular borders in a cortical location. There is a small right-sided posterior parafalcine subdural hemorrhage (arrow). The large hematoma causes marked effacement of right cerebral sulci and approximately 9 mm of subfalcine herniation. The patient underwent emergency hematoma evacuation; CAA was demonstrated at histologic analysis.
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Figure 7a. CAA-related macrohemorrhage with associated intraventricular hemorrhage in an obtunded 81-year-old man. (a) Sagittal nonenhanced T1-weighted MR image shows a large frontal cortical ICH. (b) Axial GRE MR image shows that the right-sided frontal cortical ICH extends to the right lateral ventricle. GRE images also revealed multiple cortical-subcortical microhemorrhages, a finding most consistent with a diagnosis of probable CAA. (c) Axial fluid-attenuated inversion-recovery (FLAIR) MR image shows the more rarely associated intraventricular hemorrhage (arrows) as well as subarachnoid hemorrhage (arrowhead).
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Figure 7b. CAA-related macrohemorrhage with associated intraventricular hemorrhage in an obtunded 81-year-old man. (a) Sagittal nonenhanced T1-weighted MR image shows a large frontal cortical ICH. (b) Axial GRE MR image shows that the right-sided frontal cortical ICH extends to the right lateral ventricle. GRE images also revealed multiple cortical-subcortical microhemorrhages, a finding most consistent with a diagnosis of probable CAA. (c) Axial fluid-attenuated inversion-recovery (FLAIR) MR image shows the more rarely associated intraventricular hemorrhage (arrows) as well as subarachnoid hemorrhage (arrowhead).
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Figure 7c. CAA-related macrohemorrhage with associated intraventricular hemorrhage in an obtunded 81-year-old man. (a) Sagittal nonenhanced T1-weighted MR image shows a large frontal cortical ICH. (b) Axial GRE MR image shows that the right-sided frontal cortical ICH extends to the right lateral ventricle. GRE images also revealed multiple cortical-subcortical microhemorrhages, a finding most consistent with a diagnosis of probable CAA. (c) Axial fluid-attenuated inversion-recovery (FLAIR) MR image shows the more rarely associated intraventricular hemorrhage (arrows) as well as subarachnoid hemorrhage (arrowhead).
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Microhemorrhages.—
Petechial hemorrhages ( 5 mm in size) are generally asymptomatic. Walker et al (14) found evidence of microhemorrhage in a characteristic cortical-subcortical distribution in 15.5% of elderly patients more than 70 years of age. CT and conventional or fast spin-echo T1- and T2-weighted MR imaging sequences are relatively insensitive for such small microhemorrhages.
Local magnetic field inhomogeneity related to the presence of hemosiderin in foci of petechial hemorrhage causes a marked loss of signal at T2*-weighted GRE imaging, which is currently the most sensitive sequence for detection of the cortical-subcortical microhemorrhage associated with CAA (14,22) (Fig 8).
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Figure 8. CAA-related microhemorrhage in a 76-year-old woman with memory loss, seizures, and headaches. CAA was diagnosed with biopsy at another institution. Axial GRE MR image shows multiple cortical-subcortical microhemorrhages, a finding consistent with CAA.
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The presence of these cortical microhemorrhages lends specificity in patients presenting with acute ICH.
Leukoencephalopathy
Leukoencephalopathy—low attenuation of white matter at CT or high signal intensity of white matter at T2-weighted MR imaging—is a nonspecific finding that can be due to demyelination, ischemia, infarction, or edema. CAA should be considered in the broad differential diagnosis of leukoencephalopathy, especially if associated with cortical-subcortical hemorrhage(s) or progressive dementia (11). Two imaging patterns of leukoencephalopathy in patients with CAA have been reported.
Leukoencephalopathy with Sparing of U Fibers.—
A symmetric periventricular distribution of white matter high signal intensity, sparing the U fibers and associated with atrophy, is seen in patients with a clinically protracted dementia, similar to that seen in patients with Alzheimer disease. These white matter lesions are similar to those seen in Binswanger subcortical encephalopathy and may have a similar etiology. However, in CAA, this ischemic white matter damage is presumed to be caused by diffuse narrowing of penetrating cortical vessels resulting from ß-amyloid deposition in the adventitia (10,11). Low attenuation at CT and/or high signal intensity at T2-weighted MR imaging are most prevalent in the centrum semiovale and deep white matter with sparing of the U fibers, corpus callosum, and internal capsules (Fig 9). These lesions can be both diffuse and focal and may be severe in patients with long-standing dementia. In patients with ICH, white matter lesions can be observed in regions remote from the ICH.
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Figure 9a. Leukoencephalopathy in a 79-year-old woman with slowly progressive dementia similar to Alzheimer dementia. (a, b) Axial nonenhanced CT scan (a) and FLAIR MR image (b) show symmetric periventricular leukoencephalopathy with sparing of the U fibers, corpus callosum, and internal capsules. The FLAIR image also shows encephalomalacia and hemosiderin from prior macrohemorrhage in the left frontal lobe. (c) Axial GRE MR image shows multiple bilateral cortical foci of hemosiderin, thus increasing the specificity for a diagnosis of probable CAA. The encephalomalacia and hemosiderin in the left frontal lobe are also seen.
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Figure 9b. Leukoencephalopathy in a 79-year-old woman with slowly progressive dementia similar to Alzheimer dementia. (a, b) Axial nonenhanced CT scan (a) and FLAIR MR image (b) show symmetric periventricular leukoencephalopathy with sparing of the U fibers, corpus callosum, and internal capsules. The FLAIR image also shows encephalomalacia and hemosiderin from prior macrohemorrhage in the left frontal lobe. (c) Axial GRE MR image shows multiple bilateral cortical foci of hemosiderin, thus increasing the specificity for a diagnosis of probable CAA. The encephalomalacia and hemosiderin in the left frontal lobe are also seen.
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Figure 9c. Leukoencephalopathy in a 79-year-old woman with slowly progressive dementia similar to Alzheimer dementia. (a, b) Axial nonenhanced CT scan (a) and FLAIR MR image (b) show symmetric periventricular leukoencephalopathy with sparing of the U fibers, corpus callosum, and internal capsules. The FLAIR image also shows encephalomalacia and hemosiderin from prior macrohemorrhage in the left frontal lobe. (c) Axial GRE MR image shows multiple bilateral cortical foci of hemosiderin, thus increasing the specificity for a diagnosis of probable CAA. The encephalomalacia and hemosiderin in the left frontal lobe are also seen.
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Leukoencephalopathy with Involvement of U Fibers.—
Several case reports of patients with pathologically proved CAA have described subacute cognitive decline associated with leukoencephalopathy that extends to involve U fibers and is associated with mass effect likely related to edema (9,11,23,24). At T2-weighted MR imaging, white matter high signal intensity is most prevalent in the centrum semiovale and deep periventricular regions, sparing the corpus callosum and internal capsule (Fig 10). Most cases demonstrated perivascular inflammation at biopsy. Harkness et al (23) proposed that these changes may be secondary to ß-amyloid–induced vasculopathy—cerebral amyloid inflammatory vasculopathy (CAIV). A few biopsy-proved cases of CAIV have responded to immunosuppressive therapy, with at least partial resolution of leukoencephalopathy at imaging (8,10,24).
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Figure 10a. Leukoencephalopathy in a 61-year-old woman with rapidly progressive cognitive decline. (a) Axial FLAIR MR image shows asymmetric lobar leukoencephalopathy extending to involve the U fibers and exerting mass effect on the adjacent sulci, most prominently in the posterior left parietal lobe. The absence of signal abnormality at diffusion-weighted MR imaging made an ischemic process or acute infarction unlikely. CAA was diagnosed with biopsy. (b) Axial GRE MR image obtained after biopsy shows a few cortical microhemorrhages (arrows). The patient was treated with a short course of prednisone taper therapy, which started at 40 mg and produced clinical improvement. (c) Follow-up axial FLAIR MR image obtained 1 year later shows near-complete resolution of the leukoencephalopathy. CAA patients with subacute cognitive decline and leukoencephalopathy may respond to immunosuppressive therapy.
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Figure 10b. Leukoencephalopathy in a 61-year-old woman with rapidly progressive cognitive decline. (a) Axial FLAIR MR image shows asymmetric lobar leukoencephalopathy extending to involve the U fibers and exerting mass effect on the adjacent sulci, most prominently in the posterior left parietal lobe. The absence of signal abnormality at diffusion-weighted MR imaging made an ischemic process or acute infarction unlikely. CAA was diagnosed with biopsy. (b) Axial GRE MR image obtained after biopsy shows a few cortical microhemorrhages (arrows). The patient was treated with a short course of prednisone taper therapy, which started at 40 mg and produced clinical improvement. (c) Follow-up axial FLAIR MR image obtained 1 year later shows near-complete resolution of the leukoencephalopathy. CAA patients with subacute cognitive decline and leukoencephalopathy may respond to immunosuppressive therapy.
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Figure 10c. Leukoencephalopathy in a 61-year-old woman with rapidly progressive cognitive decline. (a) Axial FLAIR MR image shows asymmetric lobar leukoencephalopathy extending to involve the U fibers and exerting mass effect on the adjacent sulci, most prominently in the posterior left parietal lobe. The absence of signal abnormality at diffusion-weighted MR imaging made an ischemic process or acute infarction unlikely. CAA was diagnosed with biopsy. (b) Axial GRE MR image obtained after biopsy shows a few cortical microhemorrhages (arrows). The patient was treated with a short course of prednisone taper therapy, which started at 40 mg and produced clinical improvement. (c) Follow-up axial FLAIR MR image obtained 1 year later shows near-complete resolution of the leukoencephalopathy. CAA patients with subacute cognitive decline and leukoencephalopathy may respond to immunosuppressive therapy.
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Atrophy
Prominence of the ventricular system and enlargement of the sulci representing generalized cerebral and cerebellar atrophy are nonspecific imaging findings, especially in the elderly. In CAA, atrophy is most likely the result of chronic small vessel ischemia related to ß-amyloid deposition and is usually seen in association with leukoencephalopathy (Fig 11a). When atrophy and leukoencephalopathy are seen in conjunction with acute or chronic ICH in a cortical-subcortical location, the diagnostic specificity for CAA is increased (Fig 11b).
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Figure 11a. Probable CAA in a 72-year-old woman with speech difficulties and waxing and waning memory loss. (a) Axial FLAIR MR image shows nonspecific atrophy as well as periventricular leukoencephalopathy and prominent left-sided parieto-occipital leukoencephalopathy. (b) Axial GRE MR image shows cortical-subcortical microhemorrhages and a small left-sided parietal cortical-subcortical macrohemorrhage. These findings increase suspicion for probable CAA.
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Figure 11b. Probable CAA in a 72-year-old woman with speech difficulties and waxing and waning memory loss. (a) Axial FLAIR MR image shows nonspecific atrophy as well as periventricular leukoencephalopathy and prominent left-sided parieto-occipital leukoencephalopathy. (b) Axial GRE MR image shows cortical-subcortical microhemorrhages and a small left-sided parietal cortical-subcortical macrohemorrhage. These findings increase suspicion for probable CAA.
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Management and Prognosis
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Although surgical intervention for an acute ICH was previously thought to be contraindicated in CAA patients because of fear of rebleeding (1), more recent studies have not shown an increased frequency of adverse outcome in most patients with CAA-related ICH. Patients 75 years of age or older, those with a hematoma in a parietal lobe location, or those with associated intraventricular hemorrhage are more likely to have an adverse postoperative outcome and should be treated nonsurgically (19,25).
Currently, there is no treatment to halt or reverse ß-amyloid deposition. Thus, attention is directed instead to the prevention of adverse outcomes associated with the natural history of CAA, such as recurrent hemorrhages or progressive dementia.
Furthermore, higher numbers of micro-hemorrhages on the baseline GRE MR images are predictive of a greater risk for recurrent bleeding, future cognitive impairment, loss of functional independence, or death (26).
Patients with a new diagnosis of CAA who receive anticoagulation for other disorders should undergo evaluation of the risks and benefits of continued anticoagulation and antiplatelet therapy. Administration of anticoagulation therapy for presumed TIA or warfarin for atrial fibrillation and other disorders may potentiate the risk of hemorrhage in a CAA patient. Rosand et al (27) found that even therapeutic levels of anticoagulation with warfarin (international normalized ratio 3) are associated with an increased frequency of warfarin-associated ICH in CAA patients. Furthermore, while warfarin has decreased the annual risk of stroke in patients more than 75 years of age from 3.5%–8.1% to less than 2%, it carries an annual rate of ICH of 1.8%, even higher in CAA patients, thus potentially offsetting the benefit of warfarin in stroke prevention (27). Other studies have shown fatal outcomes in CAA patients undergoing thrombolytic or antiplatelet therapy for various clinical indications (16). The risk-benefit ratio of anticoagulation and thrombolytic therapy in CAA patients should be carefully considered on an individual basis.
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Differential Diagnosis
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A single large cortical-subcortical ICH in a patient presenting with an acute neurologic deficit is not entirely specific for a diagnosis of CAA (16). ICH is most commonly caused by hypertension, trauma, bleeding diatheses, amyloid angiopathy, illicit drug use (mostly amphetamines and cocaine), and vascular malformations. Infrequent causes include hemorrhagic tumors, ruptured aneurysms, and vasculitis (28). The history, physical examination findings, and laboratory results often allow establishment of one of these diagnoses. However, specific characteristics of the ICH are just as important in the identification of CAA-related ICH.
Hypertension is the most common cause of nontraumatic hemorrhage in adults (29). In contrast to the typical cortical-subcortical location of CAA-related hemorrhage, hypertensive hemorrhages, both large and small, most commonly occur in the deep gray matter, such as the basal ganglia or thalami, or the brainstem (Figs 12, 13).
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Figure 12. Hypertension-related macrohemorrhage in an 80-year-old woman with right-sided weakness and a blood pressure of 160/85 mm Hg. Axial nonenhanced CT scan shows an area of increased attenuation in the left thalamus, a finding most consistent with an acute hypertensive ICH.
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Figure 13. Hypertension-related microhemorrhages in a 91-year-old woman with hypertension and unsteadiness. Axial GRE MR image shows multiple small foci of hemosiderin in both basal ganglia and thalami, locations more consistent with a hypertensive cause.
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Although a hemorrhagic tumor may exhibit a cortical-subcortical location similar to CAA-related hemorrhage, MR imaging may be helpful in identifying additional enhancing lesions, leading to a greater suspicion of metastatic disease (Fig 14).
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Figure 14a. Large macrohemorrhage in a 66-year-old man with biopsyproved brain metastases from small cell lung cancer who presented with headache, light-headedness, and difficulty walking. (a) Axial FLAIR MR image shows a large right-sided frontal cortical hematoma with surrounding vasogenic edema. A fluid-fluid level is present, as is often seen in patients undergoing anticoagulation therapy. This patient was taking clopidogrel for a coronary stent. (b) Axial contrast-enhanced T1-weighted MR image shows a second, nonhemorrhagic metastatic lesion in the right temporal lobe (arrow).
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Figure 14b. Large macrohemorrhage in a 66-year-old man with biopsyproved brain metastases from small cell lung cancer who presented with headache, light-headedness, and difficulty walking. (a) Axial FLAIR MR image shows a large right-sided frontal cortical hematoma with surrounding vasogenic edema. A fluid-fluid level is present, as is often seen in patients undergoing anticoagulation therapy. This patient was taking clopidogrel for a coronary stent. (b) Axial contrast-enhanced T1-weighted MR image shows a second, nonhemorrhagic metastatic lesion in the right temporal lobe (arrow).
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Conclusions
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CAA-related hemorrhage is an important cause of morbidity and mortality in the normotensive elderly patient. Patients may present with a spectrum of clinical findings such as sudden neurologic deficit (stroke), TIA-like symptoms, or dementia that can be seen in disorders other than CAA. However, neuroimaging demonstrates patterns of involvement that are characteristic of CAA, including cortical-subcortical location of macro- and microhemorrhages, which may be found concurrently with leukoencephalopathy and atrophy. Early recognition of the constellation of imaging findings associated with CAA facilitates a clinical diagnosis of CAA and proper patient treatment.
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Acknowledgments
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We thank Murli Krishna, MD, for contributing the pathologic slides.
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Footnotes
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Abbreviations: CAA = cerebral amyloid angiopathy, FLAIR = fluid-attenuated inversion recovery, GRE = gradient echo, ICH = intracranial hemorrhage, TIA = transient ischemic attack
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References
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Abstract
Introduction
