Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.

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Intracerebral hemorrhage (ICH), the most devastating form of stroke, has no specific therapy proven to improve outcome by randomized controlled trial. Location and baseline hematoma volume are strong predictors of mortality, but are nonmodifiable by the time of diagnosis. Expansion of the initial hematoma is a further marker of poor prognosis that may be at least partly preventable. Several risk factors for hematoma expansion have been identified, including baseline ICH volume, early presentation after symptom onset, anticoagulation, and the CT angiography spot sign. Although the biological mechanisms of hematoma expansion remain unclear, accumulating evidence supports a model of ongoing secondary bleeding from ruptured adjacent vessels surrounding the initial bleeding site. Several large clinical trials testing therapies aimed at preventing hematoma expansion are in progress, including aggressive blood pressure reduction, treatment with recombinant factor VIIa guided by CT angiography findings, and surgical intervention for superficial hematomas without intraventricular extension. Hematoma expansion is so far the only marker of outcome that is amenable to treatment and thus a potentially important therapeutic target.

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Background and Purpose The spot sign score is a potent predictor of hematoma expansion in patients with primary intracerebral hemorrhage (ICH). We aim to determine the accuracy of this scoring system for the prediction of in-hospital mortality and poor outcome among survivors in patients with primary ICH. Methods Three neuroradiologists retrospectively reviewed CT angiograms (CTAs) performed in 573 consecutive patients who presented to our Emergency Department with primary ICH over a 9-year period to determine the presence and scoring of spot signs according to strict criteria. Baseline ICH and intraventricular hemorrhage volumes were independently determined by computer-assisted volumetric analysis. Medical records were independently reviewed for baseline clinical characteristics and modified Rankin Scale (mRS) at hospital discharge and 3-month follow-up. Poor outcome among survivors was defined as a mRS ≥4 at 3-month follow-up. Results We identified spot signs in 133 of 573 CTAs (23.2%), 11 of which were delayed spot signs (8.3%). The presence of any spot sign increased the risk of in-hospital mortality (55.6%, OR4.0, 95%CI 2.6–5.9, p<0.0001) and poor outcome among survivors at 3-month follow-up (50.8%, OR2.5, 95%CI 1.4–4.3, p 0.0014). The spot sign score successfully predicted an escalating risk of both outcome measures. In multivariate analysis, the spot sign score was an independent predictor of in-hospital mortality (OR1.5, 95%CI 1.2–1.9, p 0.0002) and poor outcome among survivors at 3-month follow-up (OR1.6, 95%CI 1.1–2.1, p 0.0065). Conclusion The spot sign score is an independent predictor of in-hospital mortality and poor outcome among survivors in primary ICH.

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IMPORTANCE Hematoma expansion is an important determinant of outcome in spontaneous intracerebral hemorrhage (ICH) due to small vessel disease (SVD), but the association between the severity of the underlying SVD and the extent of bleeding at the acute phase is unknown to date. OBJECTIVE To investigate the association between key magnetic resonance imaging (MRI) markers of SVD (as per the Standards for Reporting Vascular Changes on Neuroimaging [STRIVE] guidelines) and hematoma volume and expansion in patients with lobar or deep ICH. DESIGN, SETTING, AND PARTICIPANTS Analysis of data collected from 418 consecutive patients admitted with primary lobar or deep ICH to a single tertiary care medical center between

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