Role of cerebral amyloid angiopathy in intracerebral hemorrhage in hypertensive patients
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Abstract
Objective: To assess the interaction of cerebral amyloid angiopathy (CAA) and arterial hypertension as cofactors for intracerebral hemorrhage (ICH).
Methods: The authors investigated 129 postmortem brains of hypertensive patients with and without ICH. Sixty-four patients had had deep (n = 40) or lobar (n = 24) ICH. Sixty-five patients without ICH served as controls. Established risk factors for ICH (age, gender, severity of hypertension, bleeding disorders, intake of anticoagulants, and chronic alcoholism) were identified from medical records. Four specimens per brain were stained with hematoxylin-eosin and Congo red. The entire ICH cohort and subgroups were compared with controls using single-factor and multiple logistic regression analyses.
Results: CAA was found in 15 of 64 subjects (23%) with ICH and in five of 65 controls (8%; p = 0.026). In single-factor analysis, CAA was more prevalent in lobar ICH compared with controls (p = 0.007) but not in deep ICH. Poor control of hypertension was more prevalent in the entire ICH group (p = 0.01) and in deep ICH (p = 0.016) but not in lobar ICH. ICH was predictive of the presence of CAA (odds ratio: 5.6, 95% CI: 1.8 to 19.5, p = 0.003), and CAA was more likely to be found in lobar ICH in multivariable-adjusted analysis. After adjustment for conventional risk factors, there was a weak association between CAA and deep ICH.
Conclusion: Cerebral amyloid angiopathy plays a major role in the pathogenesis of intracerebral hemorrhage even in patients with more evident risk factors.
Primary intracerebral hemorrhage (ICH) accounts for 10 to 20% of all strokes in white populations.1,2 Deep ICH and lobar ICH can be distinguished.3–7 Arterial hypertension (HT), anticoagulation medication, alcoholism, male gender, and older age are known risk factors for ICH.8–13
Deep ICH and HT are so closely linked that the term hypertensive ICH is frequently used synonymously with deep ICH. However, patients with lobar ICH also frequently have a clinically documented history of HT.5,11,12,14,15
Cerebral amyloid angiopathy (CAA) has frequently been overlooked in clinical studies as a risk factor for ICH.13 CAA is a known risk factor for lobar ICH16–18 and is suspected in older patients who do not exhibit any other of the above-mentioned risk factors.19 Alzheimer disease (AD), deep white matter lesions, and stroke are also associated with CAA,16,19–23 although the mechanism leading to white matter lesions in CAA remains unclear.
Difficulties arise if a single ICH is to be allocated to particular etiologies, but both the conventional risk factors and CAA are present. Most pathologic studies evaluating the causal relationship between lobar ICH and CAA did not systematically study the presence of competing risk factors,16–20,24–26 and studies of deep ICH did usually not search for CAA.7,9,10,12,13 The complex interaction and individual contribution of competing risk factors including CAA and HT have not been analyzed thus far.
In this histopathologic case-control study, we systematically address the role of CAA for ICH in patients with other, more conventional, risk factors for ICH.
Methods.
Subject selection.
We investigated brains of patients who had died between 1997 and 2000 in the Neurology Department of the University Hospital of Debrecen, Hungary. One hundred twenty-one patients with the admission diagnosis of ICH had died in the study period. The brains of the patients were stored in 10% formalin according to federal law in the brain archives of the Department of Neuropathology. Brains of patients in the archives were entered in chronologic order in the logbook with name, age, admission diagnosis, and accompanying diseases. We only investigated brains of hypertensive patients. Fifty-seven patients were excluded for the following reasons: 25 patients were not hypertensive, 10 patients had had subarachnoid hemorrhage, two had a vascular malformation, two had metastatic malignancies, and 15 patients had incomplete medical records. In three additional subjects, it was not possible to clarify whether a primary ICH or a hemorrhagic transformation of a primarily ischemic infarction was present. Therefore, 65 patients with primary ICH and confirmed HT were selected from the archives log. Forty-nine patients in this group had died as a direct consequence of the hemorrhage. Other reasons for death were myocardial infarction (1), pneumonia (6), multiorgan failure (3), and pulmonary embolism (5).
For each case with ICH and HT, the next consecutive patient who had died after a case patient was selected as a control if the following conditions were present: 1) patient had never had ICH, 2) patient was hypertensive, 3) patient was of a similar age (±5 years), and 4) complete medical records were available. The controls were not matched for gender. Most of the controls had had ischemic stroke on admission (53 of 65 patients, 82%). The most frequent causes of death were herniation (20), pneumonia (17), pulmonary embolism (9), and myocardial infarction (6). One patient with cerebellar ICH was excluded after the study because cerebellar ICH is difficult to assign to either the lobar or the deep ICH group. In total, there remained 64 cases and 65 controls.
Risk factor analysis.
Complete medical records including a neuropathologic examination and a full postmortem autopsy report of all subjects were available. Charts were reviewed for age, gender, control of HT, bleeding disorders, intake of anticoagulants, and chronic alcoholism. The risk factors were considered present or absent according to the algorithms below.
Arterial HT.
Subjects were only eligible for the study if they had been hypertensive. The diagnosis of HT had to be cited in the final report as well as in the autopsy report. Supportive of HT were anamnestic data (known HT, antihypertensive treatment) and findings at autopsy that indicated the presence of HT during life (left ventricular hypertrophy of the heart, elongation of the aorta or the supraaortal vessels, hypertensive nephropathy). To consider the severity, HT was classified as being controlled or uncontrolled. HT was classified as being controlled, if antihypertensive medication was regularly taken during life and no left ventricular hypertrophy or hypertensive nephropathy was reported in the autopsy report. HT was classified as uncontrolled if patients or patients’ relatives had stated that HT was not well controlled despite treatment, if medication was not at all or not regularly taken, or if autopsy revealed hypertensive end-organ changes.
Presence of a hemorrhagic diathesis.
Patient histories, as well as routine clotting screens extracted from the chart, were used for assessment. Spontaneous international normalized ratio (INR) values of >1.3, platelet counts of <100,000/μL or APTT of >40 seconds were considered pathologic if no anticoagulant medication was taken.
Anticoagulant intake was classified as present or absent based on the final report. History and, accordingly, an elevated INR value of >1.3 in routine clotting screens was used to confirm the diagnosis.
Chronic alcoholism was classified as present or absent according to its diagnosis on the final report. For confirmation, a history of chronic drinking and liver degeneration compatible with chronic drinking (cirrhosis in the absence of positive hepatitis history or titers) was used.
Location of the bleeding.
The ICHs were classified as being predominantly lobar or deep. Subcortical and cortical ICHs of the cerebral hemispheres and subinsular ICH (hematoma of the insular subcortex with close relation to the basal ganglia) were classified as lobar ICHs. ICHs of the basal ganglia, the capsula interna, and the brainstem were classified as deep ICHs. Cranial CT performed on admission of the patients was available for 109 of the 129 subjects (56 of 64 with ICH, 53 of 65 controls). To classify the location of the bleeding, CT scans were assessed if available. If no CT was available, the appearance of the ICH on gross neuropathology was assessed.
Tissue sampling and preparation.
All brains had been stored in coronal slices of ∼1 cm thickness in 10% formalin until preparation. From each brain, four to five tissue samples were taken from one side of the following regions: 1) frontoparietal lobe (junction of medial frontal gyrus and precentral gyrus), 2) occipital lobe (around calcarine fissure), 3) basal ganglia (at the coronal level of the mamillary bodies), 4) cerebellar hemisphere, and 5) tissue from the presumed area of the ICH origin, if not already covered by one of the first four samples.
In addition to the sample from the bleeding origin, the other four samples per brain were randomly taken from the left or right hemispheres. The side was determined before tissue extraction using a binary, four-digit random number generator with 1 determining the right side and 0 the left side. Tissue blocks were 1 × 1 × 1.5 cm. Care was taken to make sure that cortical samples also contained leptomeningeal tissue. The samples were embedded in paraffin and thin sections of 6 μm were cut and stained with Congo red and hematoxylin-eosin (HE).
Microscopic evaluation.
Stained thin sections were evaluated using light microscopy. The presence and severity of CAA were analyzed based on Congo red–stained samples. Fibrinoid necrosis, wall thickness, and preservation or derangement of vessel architecture was noted in HE-stained samples.
CAA was scored as being definitely present (Congo positive) if a characteristic pink or salmon-like staining was found in the vessel wall and not in the tissue itself.
We graded the severity of CAA using the method proposed by Vonsattel et al.16 scoring the severity of CAA in single arteries. In short, severity was judged using scores of 0 to 3. A score of 0 was given if there was no CAA in the entire sample, i.e., Congo negative. A score of 1 was given if the most severely affected vessels showed a thin Congo-positive rim restricted to the vessel wall (figure, A). A score of 2 was applied if the entire wall was replaced by amyloid, but the architecture of the vessel was preserved (see figure, B). A score of 3 was given if secondary changes could also be observed in amyloid-positive vessels. These changes included the presence of microbleedings, microaneurysms, fibrinoid necrosis, or a double-barrel appearance16,19,25,27 (see figure, C).
Figure. Severity grading of cerebral amyloid angiopathy. (A) Only a fine rim of salmon-like staining is found in the vessel wall. There is no change in the vessel architecture or thickening of the wall. Score = 1. Also note Alzheimer plaques in the vicinity of the vessels (arrows) (Congo red, ×100). (B) The entire wall of the vessel is dominated by Congo-positive material. There are no vessel fractures or fibrinoid necrosis or paravascular blood. Score = 2 (Congo red, ×100). (C) The vessel architecture (arrow) is destroyed. The wall is Congo positive. Fibrinoid necrosis can be seen (*). Score = 3 (Congo red, ×100; small section in upper left corner, hematoxylin-eosin. ×100).
Statistics.
The primary outcome variable was the presence of CAA in the entire ICH group compared with the non-ICH group using the χ2 test. For the secondary evaluation, the entire ICH group was divided into lobar and deep ICH. The presence of CAA was compared between subgroups and the control group using the χ2 test.
Frequency of risk factors was also assessed for the entire ICH group and for the subgroups using χ2 tests for the dichotomous variable HT management status, bleeding diathesis, anticoagulant therapy, and alcoholism. The Mann–Whitney U test was used to test for significant differences in age.
All the above factors were included in multivariate logistic regression models separately applied to the entire ICH group, the group of lobar ICH, and the group of deep ICH. For these models, age was dichotomized into age ≤ or >70 years. The decision as to which factors to include in the model was made before sample analysis including all variables shown to be important risk factors for ICH.1,7,8,13
For the comparison of CAA severity, the total scores of all investigated brain regions were calculated for each Congo-positive subject. These total scores were tested for differences between the subgroups and controls using the Mann–Whitney U test. p Values of <0.05 were considered significant.
Results.
Risk factor analysis.
Table 1 gives the detailed risk factors for all 129 subjects including p values of the statistical tests.
Table 1 Patient characteristics and single factor analysis
Single-factor analysis of the entire ICH group vs controls revealed a higher prevalence of CAA in subjects with ICH (15 of 64, 23%) than in controls (5 of 65, 8%, p = 0.026). Uncontrolled HT was also more prevalent in subjects with ICH (34 of 64, 53%) than in controls (19 of 65, 29%, p = 0.01).
Single-factor analysis of the subgroups vs controls showed more subjects with CAA in the lobar ICH group compared with controls (p = 0.007). CAA was not more prevalent in deep ICH compared with controls in single-factor analysis (p = 0.224). Uncontrolled HT was more prevalent in the deep ICH group than in controls (p = 0.016) but not in the lobar ICH group compared with controls (p = 0.11). There was a trend toward a higher prevalence of anticoagulant intake in the deep ICH group compared with controls (p = 0.055).
All recorded risk factors were included in multivariate regression analyses. The results are presented in table 2.
Table 2 Results of multiple regression analysis
The presence of CAA (odds ratio [OR]: 5.6), uncontrolled HT (OR: 3.1), and anticoagulant intake was significantly more frequent in the entire ICH group than in controls. The statistical association of CAA and lobar hemorrhage was strong (OR: 9.5;, p = 0.001) after logistic regression analysis. The association of CAA and deep ICH was weaker (OR: 4.2, 95% CI: 1.1 to 17.7; p = 0.047) but still significant. In subjects with deep ICH, uncontrolled hypertension (OR: 3.6; p = 0.008) and anticoagulant intake before hospital admission (OR: 26.9; p = 0.007) was also significantly more frequent than in controls but not in subjects with lobar ICH.
Distribution and severity of CAA.
No obvious differences in the severity total scores (Σ) of CAA in the ICH subgroups compared with the control group were detected (entire ICH: Σ = 3.2 ± 2.8, lobar ICH: Σ = 3.9 ± 3, deep ICH: Σ = 2.2 ± 2.4, controls: Σ = 3.6 ± 1.5; p ≫ 0.05).
CAA was predominantly present in the occipital and frontoparietal sections of the brains investigated. In addition, CAA tended to be most severe here whenever it was present in more than one region.
We did not find CAA in any of the basal ganglia samples but found CAA in the cerebellum of five of 20 subjects (four of 15 with ICH, one of five without ICH).
Discussion.
We systematically assessed the presence of well-known conventional risk factors for ICH and the presence and extent of CAA using a retrospective clinical and postmortem approach in a case-control study of hypertensive patients with and without ICH. By using multiple regression models, we found the presence of CAA, independent of other risk factors, to be correlated with the presence of ICH. As was expected, we also found uncontrolled HT and anticoagulant medication to be independently correlated with ICH.12,13,24 In contrast to other studies, we were not able to show significant differences between patients with ICH and controls concerning the risk factors gender, chronic drinking, and age.2,13
Most histopathologic studies concerning CAA-related ICH restricted their analysis to lobar ICH only, and the presence of other risk factors served as an exclusion criterion or was not considered in the statistical analysis.16,19,25–27 Thus, there is still uncertainty as to what extent CAA increases the risk of ICH beyond conventional risk factors. We have shown that CAA is an important and independent risk factor for ICH even if conventional risk factors are already present. Our study gives an estimate of the additional risk for ICH that patients with CAA bear. This finding also suggests that the presence of CAA should generally be taken into account when diagnosing and treating lobar ICH even if hypertension is present and suggests a dominant role for CAA in the pathogenesis of bleeding in respective cases.
Beyond this fact, there was a weak association between CAA and deep ICH. However, this relationship was much weaker than for the lobar ICH subgroup and reached significance only after adjustment for age and severity of hypertension. Although interesting, this finding needs to be reproduced in a larger series. The difference might be a purely statistical phenomenon or the result of a selection bias. The absolute number of patients with proven CAA was small in the deep ICH subgroup and in controls, and we did not find CAA in any of our specimens from the basal ganglia. This finding is in accordance with most previous studies and seems to argue against a significant role of CAA in the pathogenesis of deep ICH.16,17,19,25 The other variables of our case series were not fully in accordance with the general population of patients with ICH. Age, gender, and alcoholism were not significantly associated with ICH, suggesting that our study was underpowered to detect this difference. We were unable to demonstrate a relevant difference between the total scores of CAA severity of case and control groups and hypothesize that this was also because of the relatively low absolute number of patients with CAA in both groups. Using patients with ischemic stroke as controls constitutes a potential source of bias because ischemic stroke itself is probably associated with CAA.23 However, the frequency of CAA would possibly have been even lower in brains without cerebrovascular disease. Thus, using true normal controls could have resulted in higher ORs than those reported.
A possible pathophysiologic explanation for our findings might be that CAA and white matter lesions on MRI are correlated21 and white matter lesions are correlated with deep ICH.22 CAA might possibly lead to impaired autoregulation and impairment of the blood-brain barrier,28,29 and the transmission of potentially harmful blood pressure peaks to the small arteries of the basal ganglia and the brain stem may be facilitated. CAA might therefore increase the risk of deep ICH via indirect effects.
Footnotes
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M.A.R. was supported by grant HUN 00-007 from the German Ministry of Education and Research) and grant ETT 122/2003 of the Hungarian Science and Technology Foundation).
All authors are employees of the general health system of Germany or Hungary.
Received May 28, 2004. Accepted in final form December 13, 2004.
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