Cerebral Amyloid Angiopathy: An Underrecognized Cause of Hemorrhagic Stroke in the Elderly

Introduction

Cerebral amyloid angiopathy (CAA) is a disease of amyloid deposition within small-to-medium–sized cerebral vessels, and predisposes patients to spontaneous cerebral hemorrhage. It has become increasingly recognized as an important cause of lobar intracerebral hemorrhage (ICH) among elderly patients and is distinguished from hypertensive ICH, which usually occurs within the deep areas of the brain. Diagnosis in the clinical setting can be accomplished using clinical criteria, and there are recent data that suggest other objective means to identify patients with CAA, including gradient echo magnetic resonance imaging (MRI). Early recognition of such patients could have clear implications on the decision to start or continue anticoagulation or antiplatelet therapy. We present a case of recurrent lobar cerebral hemorrhage in an elderly patient with CAA, and provide a review of CAA-related hemorrhage.

Case Presentation

A 78-year-old woman with a history of prior hemorrhagic stroke presented to the hospital with altered mental status, dizziness, and accelerated hypertension. Her daughter noted that she was confused on the day of her admission; she measured her mother’s blood pressure, and found it to be 200/110 mm Hg, which prompted a visit to the emergency department and subsequent admission to the hospital. The patient’s medical history was notable for left temporoparietal hemorrhagic stroke 4 years earlier with resultant expressive aphasia, as well as hypertension and chronic atrial fibrillation for which she took warfarin. At the time of hospital admission, physical examination revealed the patient to be alert and oriented, with an irregular cardiac rhythm, expressive aphasia, and normal motor, cerebellar, and sensory findings. Laboratory data were notable for a mildly elevated glucose level of 190 mg/dL and international normalized ratio of 1.6. A computed tomography scan of the head revealed a right occipital hemorrhage of moderate size. As this was the patient’s second spontaneous lobar hemorrhage, neither of which occurred in the typical deep hypertensive areas of the brain, her physicians made a diagnosis of probable CAA-related hemorrhage, in accordance with Boston Criteria for Diagnosis of CAA-Related Hemorrhage (Table).¹ The patient was treated supportively and her warfarin was discontinued; she made a modest recovery thereafter.

Discussion

CAA is a common cause of lobar ICH in the elderly. It represents 15% of all ICHs in patients over age 60, and is found in up to 50% of patients over age 70 with nontraumatic cerebral hemorrhage.² Recurrent hemorrhage is a hallmark feature of the disease, with a reported 2-year recurrence rate as high as 21%.³ Moreover, the prevalence of moderate-to-severe CAA among patients over the age of 85 years has been found to be as high as 12.1%.⁴ Although a hereditary form of CAA has been described, the majority of CAA cases are sporadic.⁵ The pathogenesis underlying CAA involves deposition of amyloid-beta protein within the media and adventitia of small- and medium-sized vessels within the cerebral cortex, a process that weakens the vessel wall. Patients with the apolipoprotein E (APOE) epsilon2 or epsilon4 allele appear to be predisposed to CAA-related vasculopathy.⁶

The most common clinical manifestation of CAA is spontaneous lobar hemorrhage within the cerebral cortex, which is in contrast to hypertensive microangiopathic ICH, which usually occurs within the thalamus, midbrain, basal ganglia, or cerebellum. A notable absence of hypertension in patients with CAA-related hemorrhage is a clinical clue that can aid in the recognition of this condition, although this finding is not universal.⁷ Other clinical manifestations include transient neurologic symptoms, microhemorrhages, and dementia. Subclinical cerebral microbleeding detected on MRI is also commonly associated with the disease.⁸ Definitive diagnosis of CAA requires pathologic demonstration of amyloid vasculopathy in the cortical and leptomeningeal vessels using Congo red stain. However, the Boston Criteria proposed by Greenberg and colleagues¹ allow for clinical diagnosis of CAA using these criteria: multiple lobar, cortical, or corticosubcortical hemorrhages; age ≥60 years; and absence of any other cause of hemorrhage. In clinical circumstances where the diagnosis of CAA remains uncertain, the most useful diagnostic modality is gradient echo MRI, which can identify subclinical cerebral microbleeding. Gradient echo MRI sequences often demonstrate multiple small, chronic hemorrhagic lesions in patients with CAA. Furthermore, the burden of cerebral microbleeding detected on gradient echo MRI may be predictive of future ICH risk.⁹ This modality may also prove useful for screening purposes, as demonstrated by Walker and colleagues,¹⁰ who detected CAA-related microbleeding in 15.5% of 97 asymptomatic elderly patients using gradient echo MRI.

It is important to recognize CAA in elderly patients because of potential adverse effects of anticoagulation, antiplatelet, and thrombolytic therapies, as the case report illustrates. The most feared complication of such therapy is ICH, which carries significant mortality and morbidity. Along these lines, Rosand et al¹¹ compared the clinical, pathologic, and genetic characteristics of subjects with ICH taking warfarin versus subjects without ICH taking warfarin. Of the 11 patients with warfarin-associated ICH for whom tissue samples were available, 7 had CAA on pathologic specimens. Additionally, the APOE epsilon2 allele was overrepresented in the group with warfarin-associated ICH.¹¹ With regard to CAA and thrombolytic therapy, a review of 23 patients with thrombolysis-associated ICH in the Thrombolysis In Myocardial Infarction (TIMI) phase II study, reported that 70% were lobar hemorrhages and that 3 of 5 pathologic specimens demonstrated CAA.¹²

There are more recent data suggesting new means by which to identify patients with CAA using medical imaging and genetic markers. The use of positron-emission tomography (PET) with a carbon 11-labeled Pittsburgh compound B (¹¹C-PIB) ligand, which binds to amyloid-beta, can be used to quantify amyloid deposition within the cerebral cortex. Using this methodology, Ly and colleagues¹³ demonstrated a moderate increase of ¹¹C-PIB binding in 9 of 12 patients with CAA-related hemorrhage. Genetic testing for the presence of APOE has been shown to be effective in identifying patients who are at increased risk of recurrent hemorrhage from CAA. In a cohort of 71 elderly patients who survived a prior lobar cerebral hemorrhage, O’Donnell et al³ reported that, of the 19 subjects who had recurrent hemorrhage, 14 were carriers of the APOE epsilon2 or epsilon4 allele. Lastly, there are recent data to suggest that cerebrospinal fluid analysis may also prove useful in the diagnosis of CAA. In a recent study of 147 patients, of whom 17 had known CAA, the authors reported markedly decreased levels of amyloid-beta₄₀ and amyloid-beta₄₂ proteins within the cerebrospinal fluid of patients with CAA.¹⁴ However, while these research modalities are of interest scientifically, they are usually unnecessary for diagnosing CAA. There are no management strategies or disease-modifying therapy specific to CAA, and the management of CAA-related hemorrhage is similar to that of any brain hemorrhage. The most important issue that clinicians face in such patients is the decision to restart anticoagulation or antiplatelet therapy after the first hemorrhage. Given the high incidence of recurrent hemorrhage, especially in the setting of anticoagulation and antiplatelet therapy, a careful risk-benefit analysis should occur before such therapy is resumed. In this regard, recognition and diagnosis are crucial to identify patients who should avoid anticoagulation or antiplatelet therapy.

Conclusion

CAA is a common cause of ICH in elderly patients and is associated with a high rate of recurrence, especially in the setting of anticoagulation, antiplatelet, or thrombolytic therapy. Although a definitive diagnosis requires pathologic confirmation of congophilic material within the cortical vessels, clinical diagnosis of CAA can usually be made in elderly patients with recurrent lobar hemorrhage, as supported by the Boston Criteria for Diagnosis of CAA-Related Hemorrhage. In patients for whom the diagnosis of CAA is uncertain, gradient echo MRI demonstrating chronic cerebral microbleeding supports the diagnosis. Management of patients with probable CAA-related hemorrhage centers primarily around supportive care and avoidance of anticoagulation and antiplatelet therapy.

The authors report no relevant financial relationships.

From the Department of Internal Medicine, University of Tennessee Health Sciences Center, Baptist Hospital, Nashville.

References

1. Greenberg SM, Edgar MA. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 22-1996. Cerebral hemorrhage in a 69-year-old woman receiving warfarin [published correction appears in N Engl J Med. 1996;335(15):1167]. N Engl J Med. 1996;335(3):189-196.

2. Ellis RJ, Olichney JM, Thal LJ, et al. Cerebral amyloid angiopathy in the brains of patients with Alzheimer’s disease: the CERAD experience, Part XV. Neurology. 1996;46(6):1592-1596.

3. O’Donnell HC, Rosand J, Knudsen KA, et al. Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage. N Engl J Med. 2000;342(4):240-245.

4. Greenberg SM, Vonsattel JP. Diagnosis of cerebral amyloid angiopathy. Sensitivity and specificity of cortical biopsy. Stroke. 1997;28(7):1418-1422.

5. Levy E, Carman MD, Fernandez-Madrid IJ, et al. Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science. 1990;248(4959):1124-1126.

6. Greenberg SM, Vonsattel JP, Segal AZ, et al. Association of apolipoprotein E epsilon2 and vasculopathy in cerebral amyloid angiopathy. Neurology. 1998;50(4):961-965.

7. Ferreiro JA, Ansbacher LE, Vinters HV. Stroke related to cerebral amyloid angiopathy: the significance of systemic vascular disease. J Neurol. 1989;236(5):267-272.

8. Vernooij MW, van der Lugt A, Ikram MA, et al. Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurology. 2008;70(14):1208-1214.

9. Greenberg SM, Eng JA, Ning M, Smith EE, Rosand J. Hemorrhage burden predicts recurrent intracerebral hemorrhage after lobar hemorrhage. Stroke. 2004;35(6):1415-1420.

10. Walker DA, Broderick DF, Kotsenas AL, Rubino FA. Routine use of gradient-echo MRI to screen for cerebral amyloid angiopathy in elderly patients. AJR Am J Roentgenol. 2004;182(6):1547-1550.

11. Rosand J, Hylek EM, O’Donnell HC, Greenberg SM. Warfarin-associated hemorrhage and cerebral amyloid angiopathy: a genetic and pathologic study. Neurology. 2000;55(7):947-951.

12. Sloan MA, Price TR, Petito CK, et al. Clinical features and pathogenesis of intracerebral hemorrhage after rt-PA and heparin therapy for acute myocardial infarction: the Thrombolysis in Myocardial Infarction (TIMI) II Pilot and Randomized Clinical Trial combined experience. Neurology. 1995;45(4):649-658.

13. Ly JV, Donnan GA, Villemagne VL, et al. 11C-PIB binding is increased in patients with cerebral amyloid angiopathy-related hemorrhage. Neurology. 2010;74(6):487-493.

14. Verbeek MM, Kremer BP, Rikkert MO, Van Domburg PH, Skehan ME, Greenberg SM. Cerebrospinal fluid amyloid beta(40) is decreased in cerebral amyloid angiopathy. Ann Neurol. 2009;66(2):245-249.