Background
Early treatment with intravenous tissue plasminogen activator (IV tPA) (< 4.5 h from symptom onset) increases the proportion of patients who survive with a favorable outcome after ischemic stroke [
1]. Though treatment is associated with better outcomes, the most feared complication is hemorrhagic transformation (HT), or bleeding into the area of ischemia when the tissue is reperfused. When the ischemic volume is large enough, this can result in a symptomatic intracerebral hemorrhage (sICH) that worsens morbidity and mortality [
2,
3].
Cerebral microbleeds (CMBs) are small areas of signal void, 2–10 mm in diameter [
4‐
6] that can be seen on gradient echo magnetic resonance imaging (MRI) sequences, mostly representing blood products commonly associated with disorders such as hypertension or cerebral amyloid angiopathy (CAA). Along with other known risk factors for hemorrhage such as age, renal disease, and stroke volume [
7], CMBs may also be associated with hemorrhage risk [
8,
9] .The reported prevalence of CMBs on pre-IV tPA imaging ranges from 15 to 40% [
10,
11]. This is clinically relevant, as it is becoming increasingly common to perform an MRI as part of the acute work-up of ischemic stroke [
12]. In addition, there is increasingly rapid electronic access to patient’s prior MR imaging that may show incidental CMBs. Understanding the associated risk of sICH may, therefore, be of significant clinical impact when considering the use of thrombolytics.
There is an existing literature on the association between CMBs and intracerebral hemorrhage with varying results [
10,
13‐
16]. This discordance between studies may be due to the varied methodologies. Increased burden and patterns of location have been analyzed differently across studies, or not at all. Of note, higher CMB burdens, particularly in the lobar location, are more highly suggestive of CAA, as described by the Boston criteria [
17], and may indicate a group of individuals at a higher risk of HT following thrombolysis. There may be other factors that are helpful in determining the likelihood of CAA over hypertension and related relative risk associated with each.
The use of thrombolytic therapy in the acute setting of ischemic stroke continues to grow and information regarding a patient’s CMB status is more commonly known. Given the lack of consensus in the literature regarding the relationship between CMBs and sICH in this study, we examine the association of CMBs with hemorrhage, taking into account presence, burden, location, and the likelihood of CAA, to predict hemorrhage in patients treated with IV tPA.
Discussion
This study was designed to evaluate the relationship between the presence, burden, and location of CMBs and HT following treatment with IV tPA for acute ischemic stroke. Our sICH rate was low at only 2%, but comparable to what has been reported in a prior multicenter stroke thrombolysis register of 7% [
7] and a national registry of 5% [
23]. Consistent with prior studies, we found that older patients, with larger [
24], more clinically severe strokes [
11,
25], lower platelet counts [
26,
27], and a history of atrial fibrillation [
11] were more likely to develop any HT; while a high CMB burden (> 10 CMBs) was the only predictor of sICH.
Looking specifically at the relationship between CMB and hemorrhage, we found an association between high CMB burden and sICH that is consistent with previously published studies. The 10 CMBs threshold was chosen based on the methodology of two recent meta-analyses and a recent multicenter trial [
14,
15,
28]. Rates of sICH were comparable across studies: those without CMBs 2% [
15] (ours: 1%), mild-moderate burden 6% [
15] (ours: 3%), and high burden 29–50% [
14,
15] (ours: 33%). One possible explanation is that these individuals had CAA, putting them at higher risk for hemorrhage due to their underlying vascular pathology.
The advantage of our smaller study was the ability to explore the association between patterns of CMB and the diagnosis of CAA, on hemorrhage risk in a population, while determining the absolute risk within a stroke cohort of similar size and composition to many urban hospital settings. Most prior meta-analyses did not take the diagnosis of CAA into account within their analyses. In our study, only 3 patients were diagnosed with CAA, but of these, one (33%) had a hemorrhage that was symptomatic. Higher numbers of CMBs may indicate a higher propensity for the breakdown of the blood brain barrier, or “leaky vessels” that may also predispose to greater risk of HT. A recent meta-analysis including CAA in its analysis supports an association between greater numbers of CMB and increased rates of HT [
29].
In our population, 21% of patients had at least one CMB present on imaging, consistent with previously published rates. While this observation might suggest that we should screen for the presence of microhemorrhages when considering treatment, it is also important to point out that CMB presence alone was not associated with either HT or sICH, and that the number of patients with > 10 CMB was very low (
n = 3, 1%), consistent with prior cohorts [
15]. Additionally, despite a CMB prevalence of 1 in 5, our rate of sICH rate was very low. These results suggest that the presence of CMBs by itself should not be considered a predictor for sICH and that MRI in the acute setting to evaluate for their existence is likely unnecessary given low rates of numerous CMBs.
Our findings are consistent with many prior studies; [
10,
16] however, three recent large meta-analyses [
13,
15,
29] do report CMB presence as an independent risk factor for HT. These meta-analyses were large, and predominantly used univariable modeling to evaluate a relationship between HT and only the presence of microbleeds. Data were described mainly in aggregate, with wide confidence intervals, as they were unable to account for population characteristics varying by center [
30]. Charidimou and colleagues did evaluate CMB burden and found, similar to our study, that larger numbers were associated with increasing hemorrhage risk and poorer outcome [
29]. Along with our study, these studies all emphasize that larger numbers of microbleeds, in many cases suggestive of CAA, is associated with HT, but that the rate of hemorrhage after tPA is low enough that a very large number of patients must to be treated to see the effect, calling into question the true clinical significance.
We also considered the importance of the location of CMBs with respect to the likelihood of HT. Our findings indicate that location is not independently associated with either symptomatic or any HT. Though this finding might also be secondary to our sample size, previous groups have had similar results [
11,
15,
16,
28].
The importance of determining the association between CMB and HT after treatment with IV tPA is increasing. Historically, non-contrast head CT has been preferred over MRI in the work-up of acute stroke due to increased availability, lower cost, and more rapid time acquisition [
31]. However, the use of MRI as part of the acute stroke work-up, as well as the number of patients who have had a previous MRI for another clinical indication and whose CMB status is known, is growing [
12]. Understanding the relationship between CMB and HT is, therefore, critical. We have shown that individuals with a high CMB burden do have an increased risk of sICH after treatment with IV tPA; however, that the absolute risk is quite low and in most cases should not preclude treatment. While risk quantification provides clinicians with the data to make informed decisions regarding the risk/benefit ratio, other variables such as stroke size and severity, and age of the patient should continue to be the key factors driving treatment decisions [
32,
33].
Our study is not without limitations. Our sample size was relatively small, potentially limiting the strength of our results due to a lack of statistical power rather than lack of an association; and from two academic tertiary referral centers in an urban setting, a distinct population. However, our population is similar to many stroke centers across the United States; and, despite a small number of sICH events, our cohort allows real life clinical application of the post-thrombolytic hemorrhage risk, both symptomatic and asymptomatic, associated with CMBs to centers of similar or smaller size and composition. In addition, for the majority of cases, imaging sequences were obtained post-IV tPA, which does not differentiate between CMBs present before IV tPA and those which appear afterward. Post-IV tPA MRIs may not be the ideal method to document CMBs due to the fact that new CMBs have been documented to occur during the first 7 days after acute ischemic stroke symptom onset in 5–13% of patients [
34‐
36]. However, considering that for our study that would mean an additional 14–38 individuals did not have CMB on admission, we feel that our results nicely illustrate both the relatively low rate of CMB on presentation,
and more importantly the low risk of sICH regardless of microbleed status, rendering screening prior to treatment an unnecessary use of both time and resources.