Cerebral Amyloid Angiopathy and Brain Hemorrhage

By Santosh Murthy, MD

Assistant Professor of Neurology, Weill Cornell Medical College

SYNOPSIS: When comparing the time course of hematoma expansion between deep hematomas and lobar hematomas from cerebral amyloid angiopathy (CAA) and other etiologies, lobar hematomas from CAA show greater expansion and a longer period of risk for hematoma growth compared to deep hematomas.

SOURCE: Seiffge DJ, Polymeris AA, Kang Law Z, et al. Cerebral amyloid angiopathy and the risk of hematoma expansion. Ann Neurol 2022;92:921-930.

Nontraumatic intracerebral hemorrhage (ICH) is the most disabling type of stroke, with the highest morbidity and mortality. One of the most important prognostic markers is hematoma expansion, which is associated with a more than four-fold odds of poor outcome after ICH. Consequently, hematoma expansion has been a therapeutic target for acute ICH intervention trials. Peak hematoma expansion occurs in the first three hours after symptom onset, and continues to steadily plateau until the end of the first 24 hours. Factors independently associated with hematoma expansion include initial hematoma volume, antithrombotic medication use, time from initial neuroimaging, and presence of the spot sign on computed tomography (CT) angiography. However, the biology of lobar and non-lobar ICH is different. Even lobar ICH has different etiologies, including cerebral amyloid angiopathy (CAA), a common cause of ICH in the elderly. It is unclear if ICH etiologies, such as CAA, differentially influence hematoma expansion.

In this context, this study by Seiffge and colleagues, published in the Annals of Neurology, offers novel insight into the relationship between CAA-related ICH and hematoma expansion. The authors performed a post-hoc analysis of the TICH-2 trial (Tranexamic Acid for Hyperacute Primary Intracerebral Hemorrhage), where exposure was a diagnosis of CAA and the outcomes were hematoma expansion between baseline and 24-hour CT scans and favorable functional outcomes at three months (modified Rankin scale score 0-2).

Among 2,298 ICH patients, 1,637 had a deep ICH and 661 had a lobar ICH, with 202 patients having CAA. Rates of hematoma expansion were the highest among the CAA-lobar ICH patients (50%), followed by non-CAA lobar ICH (37.5%), and, finally, deep ICH groups (27%). Although the primary analyses did not reveal an association between type of ICH and outcomes, a notable finding was that, among patients with a lobar CAA-ICH, there was a significant interaction of lobar CAA-ICH with time from symptom onset to randomization (increasing with time) and between CAA-ICH and baseline ICH volume (constant risk).

Regardless of ICH location, administration of tranexamic acid was associated with lower odds of hematoma expansion, but it did not influence functional outcomes. Notable limitations to consider are selection bias limiting generalizability and residual confounding from tranexamic acid use.

COMMENTARY

Hematoma expansion has been the target for acute ICH trials involving intensive blood pressure reduction and administration of hemostatic therapies. Given that hematoma expansion traditionally has been viewed as a hyperacute phenomenon, the focus has been on interventions in a time-sensitive manner. Recent studies have shown that deep ICHs have more hematoma expansion compared to lobar ICH, but the timing of this expansion is poorly studied in ICH subtypes.

In that regard, this secondary analysis of the TICH-2 trial, with nearly 2,300 ICH patients, sheds more light on hematoma expansion in different ICH etiologies. First, although baseline ICH volume previously has been shown to be associated with hematoma expansion in that larger ICH volumes have more hematoma expansion, this relationship appears only true in deep ICH and lobar non-CAA ICH patients. On the contrary, in lobar CAA ICH, baseline ICH volume shares an inverse association with hematoma expansion.

Second, hematoma expansion has been shown to decrease over time in the first 24 hours. The study by Seiffge et al confirms that this only may be true in deep ICH and lobar non-CAA ICH, but not necessarily in CAA-ICH. In fact, the odds of hematoma expansion increase over time, at least in the first eight hours or so, in patients with a lobar CAA-ICH. The authors hypothesize that leptomeningeal arteries, which bleed in CAA, may be less amenable to vasoconstriction unlike the deep penetrating arterioles that rupture in deep or non-CAA ICH.

Third, tranexamic acid appears to have a benefit on hematoma expansion but does not translate to good outcomes. This message is consistent with the results of the FAST (Efficacy and Safety of Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage) trial, which used recombinant activated factor VII. The findings of this study have important implications for future research in that patients who experience a lobar CAA-ICH have a longer time window for intervention to limit hematoma expansion compared to those who have non-CAA lobar or deep ICH.