Risk for Intracerebral Hematoma Expansion-More Than Just the Spot Sign.

Many intracerebral hemorrhages (ICHs) are still expanding at the time of initial emergency department assessment, causing increased disability or death. Although it has been frustratingly difficult to achieve clinically meaningful reductions in hematoma expansion (HE),1 it nevertheless remains an important potential treatment target to improve ICH outcomes. Ongoing contrast extravasation at the time of computed tomographic angiography can be visualized as the “spot sign.”2 These spots presumably reflect a fast rate of ongoing bleeding, as do larger spots compared with smaller spots.3 However, is rate of bleeding the only factor in HE, and is the spot sign the only neuroimaging prognosticator? In this issue of JAMA Neurology, Boulouis and colleagues4 present data demonstrating that magnetic resonance imaging (MRI) features of small vessel disease are also associated with HE after controlling for the presence or absence of the spot sign. In their retrospective analysis of 696 patients with ICH from 2000 to 2012 at a single hospital, 418 (60.1%) underwent MRI during the acute-phase hospitalization and were evaluated for signs of cerebral small vessel disease, including cerebral microbleeds (CMBs), cortical superficial siderosis, and white matter hyperintensity of presumed vascular origin. Hematoma expansion on follow-up computed tomography (CT) could be analyzed in 321 of 418 patients (76.8%). Appropriately, analyses were stratified by lobar vs deep brain location because the risk factors and causes of bleeding vary by location, with cerebral amyloid angiopathy (CAA) being a major but not exclusive cause of lobar ICH. The absence of microbleeds was associated with larger initial ICH volume in both the lobar and deep ICH groups and was associated with HE in the lobar ICH group. Cortical superficial siderosis was associated with larger lobar ICH volume. It bears repeating that the absence of CMBs, not their presence, was associated with larger ICHs in both ICH types and with HE in the lobar ICH group. This result may seem counterintuitive because patients with more CMBs have more severe vasculopathy. It also contrasts with the finding by Boulouis and colleagues4 that cortical superficial siderosis, a consequence of prior bleeds from CAA-laden leptomeningeal vessels, was associated with larger lobar ICH volume. Other smaller cohorts have provided conflicting information on whether CMBs are associated with higher or lower ICH volumes or with HE. Similar to the study by Boulouis and colleagues,4 an analysis of 151 patients with deep ICH also found that more CMBs were associated with smaller ICH volumes.5 The authors of a study6 among 59 patients observed that the absence of CMBs was associated with a greater likelihood of the spot sign, the strongest risk factor for HE. In contrast, another study7 of 181 patients demonstrated that the presence of CMBs was associated with larger lobar and deep ICH volumes, and a small study8 of 44 patients showed that HE was more common in individuals with more than 10 CMBs than in those with 1 to 10 CMBs. The reasons for the differing results are unclear but could be related to different study populations, varied assessment methods, or the role of chance. These studies, including the present study by Boulouis and colleagues,4 may be vulnerable to biases that are hard to avoid, including a lack of MRI and follow-up in many patients. In the investigation by Boulouis and colleagues,4 MRI was performed a median of 2 days after admission, at which time HE would have already ceased. This timing makes it theoretically possible that HE could have been a cause, not a consequence, of the MRI findings; however, it seems unlikely that HE could have erased CMBs, and the authors were careful not to misattribute perihematoma subarachnoid blood as cortical superficial siderosis. Cerebral microbleeds are clearly associated with increased risk of incident and recurrent ICH. So, why would a neuroimaging feature associated with risk of new vessel rupture be associated with less bleeding once a rupture occurs? The answer may be related to factors that promote or limit HE independent of the bleeding rate from the initially ruptured vessel. Hematoma expansion is promoted by a faster rate of bleeding but is limited by coagulation, local pressure that tamponades the vessel, and resistance to secondary ruptures.9 Some patients exhibit pathological and radiological evidence of multiple bleeding sites,10,11 suggesting that a chain reaction can occur in which an expanding hematoma physically displaces nearby vessels, shearing them and creating new bleeding sites. Up to 18% of ICHs have multiple spot signs, providing in vivo proof of concept that this chain reaction process can occur but is perhaps not inevitable and not present in all patients.11 Highly diseased small vessels stiffened by collagen and fibrin deposition may actually be more resistant to physical deformation and therefore less likely to be sheared by an expanding hematoma. In CAA, the presence of β-amyloid may also serve as a scaffold that reinforces the diseased vessel wall. In a small autopsy series of patients with CAA, higher CMB counts were indeed associated with thicker vessel walls.12 Therefore, the presence of CMBs may identify patients with thick vessel walls resistant to deformation and secondary rupture, Related article Opinion