Lina Palaiodimou, MD
Recently, there is increasing interest regarding available therapeutic options that can restrict hematoma expansion after spontaneous intracerebral hemorrhage (ICH) and may contribute to improved functional outcomes. Despite the initial enthusiasm in different therapeutic strategies (tranexamic acid, blood pressure lowering medication, etc.), the efficacy of such an approach has not been validated in the context of a randomized controlled clinical trial.
The question arises, whether these disappointing results would be different, if inclusion criteria were stricter (narrower time window) or based on patient selection using specific biomarkers. One proposed radiological biomarker is the presence of intrahematoma hypodensities (HD), which are defined as any hypodense region inside the hematoma, as seen in a non-contrast computed tomography (NCCT), having any morphology and size, disconnected from surrounding brain parenchyma. Another biomarker is the spot-sign (SS), which can be seen in a CT angiography (CTA) and is defined as presence of at least one focus of contrast, pooling within the hemorrhage and lack of connection with normal or abnormal vessels surrounding the hemorrhage. Both of these biomarkers have been shown to independently predict hematoma expansion in ICH and can be obtained by readily available imaging techniques.
Morotti et al examined the hypothesis that patients with ICH, presenting with both of the above radiological markers, have higher risk for hematoma expansion, in comparison with having none or just one biomarker.
Their single-center retrospective cohort study included patients presenting with ICH, for whom baseline and follow-up (at 48 hours) NCCT and CTA were available. Patients with post-traumatic ICH, existence of a secondary cause of the hemorrhage, hemorrhagic transformation of an ischemic stroke, primary intraventricular hemorrhage, surgical hematoma evacuation before having the follow-up NCCT, and with missing clinical and demographic data were excluded.
Two blinded investigators reviewed all NCCT and CTA images of the 745 patients included in the study, checking for presence of HP or SS or both. Patients were then classified into 4 groups, based on whether or not they presented any of the aforementioned markers. Four hundred sixty patients did not present any of the radiological markers (SS-HD-), CTAs revealed spot-sign in 62 patients which were HD negative on NCCTs (SS+HD-), 124 patients had intrahematoma hypodensities but not SS (SS-HD+) and 99 patients presented both markers (SS+HD+). Clinical and demographical data, such as baseline ICH volume, time from onset to NCCT, prior anticoagulant treatment, prior antiplatelet treatment, baseline Glasgow Coma Scale and presence of intraventricular hemorrhage were also stated and included in a multivariable logistic regression. The main outcome of the analysis was hematoma expansion defined as absolute hemorrhage growth >6mL or relative hemorrhage growth >33% from baseline ICH volume.
The study demonstrated that the hematoma expansion rate was significantly higher in subgroups SS+HD- (25.8%) or SS-HD+ (27.4&) when compared with SS-HD- (9.3%), a result that came as no surprise. What is more important, the researchers managed to prove that patients with combined presence of SS and HD had the highest risk of ICH expansion amongst all groups (51.5%), confirming their initial hypothesis. More specifically, ICH expansion rate was fivefold higher in patients with both the markers in comparison to those with none of them. These findings were also confirmed, when (1) a different definition of ICH expansion was used, (2) warfarin-associated hemorrhages were excluded, (3) analysis was restricted to early presenting patients (time from onset to baseline NCCT ≤ 6 hours), (4) patients with unknown last-seen-well time were excluded, and (5) admission blood pressure was adjusted in the multivariable logistic regression model. Combined evidence of SS and HD also led to improvement in specificity, regarding hematoma expansion prognosis.
The following study limitations should be considered: retrospective non-randomized study design, moderate sample size and lack of external validation of the reported findings in an independent cohort. The main limitation of this study was that the overall accuracy improved only by 4% and 7%, when combining the two imaging biomarkers compared to using SS and HD alone respectively.
In conclusion, the study by Morotti et al showed that the integration of SS and HD improves stratification of ICH expansion risk. The combined use of these two markers is proposed as a patient selection tool in clinical trials that are aiming at limiting the hematoma expansion in the acute phase of ICH. What is more, it may be used in clinical practice, imposing more intensive neurological monitoring for patients presenting at higher risk for hematoma expansion.
